Method of enhancing the expression of apolipoprotein AI using olefin derivatives

ABSTRACT

Compounds having an activity to enhance the expression of apoAI are provided. Compounds of formula (I): 
                         
in which Ar 1  and Ar 2  are independently a phenyl, naphthyl, or monocyclic or bicyclic aromatic heterocyclic group, which may be optionally substituted; —X— is —N═CZ 2 —, —CY 2 ═CZ 2 —, —CY 2 Y 3 —CHZ 2 —, —S—, —O—, or the like; Y 1 , Y 2 , Y 3 , Z 1  and Z 2  are independently a hydrogen, a halogen, a lower alkyl, a phenyl, or the like; Z 1  and Z 2  may be independently a linker group that may combine with Ar 2  and Ar 1  to form a condensed ring; m is 0 or 1, and n is 0 to 2; a prodrug thereof, a pharmaceutically acceptable salt or solvate thereof; are disclosed.

FILED OF THE INVENTION

This invention relates to a method for enhancing the expression ofapolipoprotein AI, and novel compounds therefor.

BACKGROUND ART

Cholesterol is well known as a main etiologic factor forarteriosclerosis that causes severe heart diseases. Especially,increased levels of serum low density lipoprotein (LDL) are believed tobe a definite risk factor for coronary heart diseases (CHDs). Remediesfor decreasing the level of LDL-cholesterol (LDL-C) in plasma by use ofstatins have been shown to be clinically effective in preventing theonset of CHDs and improving the conditions of CHDs and survivals inpatients suffering from hypercholesterolemia. However, about 40% of CHDspatients have a normal level of LDL-C, and are not always curedeffectively by remedies for decreasing the level of LDL-C. On the otherhand, it has been known that a half of CHDs patients having a normallevel of LDL-C shows a lower level of high density lipoprotein (HDL)cholesterol (HDL-C).

Recently, the lower level of serum HDL-C has been shown to be anadditional risk factor of the onset and the recurrence of CHD.

HDL plays an important role in reverse cholesterol transport system thatis known as a biological mechanism to transfer an excess cholesterol incells back to liver so as to maintain the level of cholesterol in livingbodies normally.

Lipoproteins such as HDL is mainly comprised of lipids and proteinscalled apoprotein, and HDL comprises an apoprotein as referred toapolipoprotein AI (hereinafter, made up by apoAI) as a main component.

Excess free cholesterols (FCs) and phospholipids in peripheral cells areextracted by free apoAI to form lipoproteins called preβ-HDL(s). Theexcess FCs integrated in the preβ-HDLs are transformed into cholesterylesters (CEs) by lecithin:cholesterol acyl transferase (LCAT), while thepreβ-HDLs increase in their particle size to mature into spherical HDLs(HDL3s). The matured HDLs are classified into diverse subfractions basedon the density, and these particles further grow up to form HDL2(s). CEsare continuously transferred into very low density lipoprotein (VLDL)and LDL by means of cholesteryl ester-transporter protein (CETP). Thoselipoproteins that integrate CEs are finally taken into the liver viareceptors. During the course, apoAI is regenerated, and again interactswith peripheral cells to repeat the extraction of cholesterols and theregeneration of preβ-HDLs.

It has been well understood that HDL plays a central role in reversecholesterol transport system and is a defensive factor ofarteriosclerosis. It is expected that agents that promote the HDLfunctions could be clinically effective as medicaments for treatingarteriosclerotic diseases. Accordingly, studies to develop agents thatenhance the level of HDL in plasma have been conducted via variousapproaches.

Among them, one of the most promising approaches is to enhance the serumlevel of apoAI, a main component of HDL. It is acknowledged that apoAIproduction increased by enhancing the expression of apoAI gene leads todirectly the elevation of HDL-C level in plasma, resulting in theactivation of reverse cholesterol transport system. In fact, it has beendemonstrated that the mRNA level of apoAI in liver correlates closelywith the levels of apoAI and HDL-C in blood (Dueland S., France D., WangS L., Trawick J D., and Davis R A., J. Lipid Res., 38:1445-53 (1997),“Cholesterol 7alpha-hydroxylase influences the expression of hepaticapoA-I in two inbred mouse strains displaying different susceptibilitiesto atherosclerosis and in hepatoma cells.”). In addition, it has beenshown that apoAI-transgenic mice and rabbit pathologic modelsadministered with apoAI exhibit anti-arteriosclerosis activities (RubinE. M., Krauss R. M., Spangler E. A., Verstuyft J. G., and Clift S. M.,Nature 353, 265-267 (1991), “Inhibition of early atherogenesis intransgenic mice by human apolipoprotein AI.”; Plump A. S., Scott C. J.,Breslow J. L., Proc. Natl. Acad. Sci. USA., 91, 9607-9611 (1994), “Humanapolipoprotein A-I gene expression increases high density lipoproteinand suppress atherosclerosis in the apolipoprotein E-deficient mouse.”;Miyazaki A., Sakuma S., Morikawa W., Takiue T., Miake F., Terano T.,Sakai M., Hakamata H., Sakamoto Y., et al., Arterioscler. Thromb. Vasc.Biol., 15, 1882-1888 (1995), “Intravenous injection of rabbitapolipoprotein A-I inhibits the progression of atherosclerosis incholesterol-fed rabbits.”).

All these facts clearly suggest that agents that enhance the expressionof apoAI would be candidates for medicaments of dyslipidemia,arteriosclerotic diseases, and other diverse diseases associated withHDL.

Compounds that increase apoAI are described in Japanese PatentPublication (kokai) No. 221959/1993, Japanese Patent Publication (kokai)No. 291094/1996, and WO97/09048, but those compounds are different fromthe compounds according to the present invention in terms of chemicalstructure.

Structurally similar compounds to those described in the invention havebeen disclosed in WO97/32574, Japanese Patent Publication (kokai) No.175965/1989, Japanese Patent Publication (kokai) No. 34967/1991, Tet.Lett., 1974, 36, 3151, Japanese Patent Publication (kokai) No.50930/1992, Collect. Czech. Chem. Commun., 1975, 40, 1892, WO96/39387,WO98/52941, WO99/02497, and U.S. Pat. No. 5,919,970, however an activityto enhance the expression of apoAI has not been described.

DISCLOSURE OF THE INVENTION

The present invention is directed to methods for enhancing theexpression of apoAI, and novel compounds having the activity thereof.

Specifically, the invention provides

-   -   1) A method of enhancing the expression of apoAI, which        comprises administrating a therapeutically effective amount of a        compound of formula (I):

in which

-   -   Ar¹ and Ar² are independently a phenyl that may be optionally        substituted, a naphthyl that may be optionally substituted, or a        monocyclic or bicyclic aromatic heterocyclic group that may be        optionally substituted;    -   —X— is a group of formula (α):

wherein

-   -   the broken line is the presence or absence of a bond;    -   -Q= is a group of

when the broken line is the present of a bond;

-   -   the wavy line represents a cis- or trans-geometrical isomerism        with respect to the double bond; and    -   -Q- is —CY²Y³— or —NY⁴— when the broken line is the absence of a        bond;        or —X— is -β- wherein -β- is —CY²Y³—, —NY⁴—, —S— or —O—;    -   Y¹, Y², Y³, Z¹ and Z² are independently a hydrogen, a halogen, a        lower alkyl that may be optionally substituted, a carboxy, a        lower alkoxycarbonyl that may be optionally substituted, a        cyano, a monocyclic carbocyclic group that may be optionally        substituted, or a monocyclic heterocyclic group that may be        optionally substituted, and two Y¹s or more and two Z¹s or more        each may be different one another;    -   Y⁴ is a hydrogen or a lower alkyl;    -   Z¹ and Z² may be independently a linker group comprising 1 to 2        atoms that may combine with the constituent atoms of the rings        Ar² and Ar¹ that are bonded to Z¹ and Z², via the two atoms        respectively, to form a condensed ring;    -   m is 0 or 1;    -   n is 0, 1, or 2; provided that, when n is 0, then m is 1 and —X—        is a group of formula (α);    -   the wavy line represents a cis- or trans-geometrical isomerism        with respect to the double bond;    -   provided that, when both Ar¹ and Ar² are a phenyl that may be        optionally substituted, then none of Y¹, Y², Z¹ and Z² are a        phenyl that may be optionally substituted; a prodrug thereof, a        pharmaceutically acceptable salt or solvate of them to a patient        expected to enhance the expression of apoAI;    -   2) The method according to above 1), in which at least one of        Ar¹ and Ar² in formula (I) is a monocyclic or bicyclic aromatic        heterocyclic group that may be optionally substituted, and that        contains a nitrogen atom at the position adjacent to the        constituent atom of the ring that has a binding bond;    -   3) The method according to above 1), in which at least one of        Ar¹ and Ar² in formula (I) is 2-pyridyl, 2-quinolyl,        2-quinoxalyl, 2-benzisoxazolyl, 2-benzothiazolyl, or        2-benzimidazolyl, each of which may be optionally substituted;    -   4) The method according to above 2) or 3), in which one of Ar¹        and Ar² in formula (I) is a group as defined in above 2) or 3),        and the other is a phenyl that may be optionally substituted, or        a monocyclic or bicyclic aromatic heterocyclic group that may be        optionally substituted;    -   5) The method according to above 2) or 3), in which one of Ar¹        and Ar² in formula (I) is a group as defined in above 2) or 3),        and the other is a phenyl or a monocyclic or bicyclic aromatic        heterocyclic group, each of which may be optionally substituted,        wherein the substituent is a halogen; a lower alkyl optionally        substituted by a halogen or a lower alkoxy; a hydroxy; a lower        alkoxy; a phenyloxy; a naphtyloxy; an acyloxy; a carboxy; a        lower alkoxycarbonyl; an amino optionally substituted by a lower        alkyl or a lower acyl; a phenyl that may be optionally        substituted by a lower alkoxy; a nitro; a lower alkylthio; a        cyano; a monocyclic heterocyclic group; or an alkylenedioxy that        may be substituted by a lower alkyl, a lower alkoxy or phenyl;    -   6) The method according to any one of above 1) to 5), in which        Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen;    -   7) The method according to any one of above 1) to 6), in which        Z¹, and Z² in formula (I) is a hydrogen;    -   8) The method according to any one of above 1) to 6), in which        Z¹ in formula (I) is a linker group comprising 1 to 2 atoms that        combines with the constituent atoms of the ring Ar² that are        bonded to Z¹ via the two atoms to form a condensed ring;    -   9) The method according to any one of above 1) to 7), in which m        in formula (I) is 1, —X— is a group of formula (α), the broken        line is the presence of a bond, -Q= is a group of

and

-   -   Y² is a hydrogen;    -   10) The method according to any one of above 1) to 6), in which        m in formula (I) is 1, —X— is a group of formula (α), and Z² is        a linker group comprising 1 to 2 atoms that combines with the        constituent atoms of the ring Ar¹ to form a condensed ring;    -   11) The method according to any one of above 1) to 7), in which        m and n in formula (I) are 1, and —X— is -β-;    -   12) A method of prevention or treatment of dyslipidemia or        arteriosclerotic diseases, which comprises administrating a        therapeutically effective amount of a compound of formula (I) as        defined in above 1), a prodrug thereof, a pharmaceutically        acceptable salt or solvate of them to a patient suspected to        have dyslipidemia or arteriosclerotic diseases; preferably the        method thereof which comprises administrating a therapeutically        effective amount of the compound as defined in any one of        above 2) to 11), a prodrug thereof, a pharmaceutically        acceptable salt or solvate of them;    -   13) A compound of formula (II):

in which

-   -   Ar² is 3-pyridyl, furyl, thienyl, pyrrolyl, or thiazolyl, each        of which may be optionally substituted; a prodrug thereof, a        pharmaceutically acceptable salt or solvate of them;    -   14) The compound according to above 13), in which the group:

is 2-pyridyl; a prodrug thereof, a pharmaceutically acceptable salt orsolvate of them;

-   -   15) The compound according to above 13) or 14), in which Ar² is        3-pyridyl, 3-furyl, 3-thienyl, or 1,3-thiazol-2-yl; a prodrug        thereof, a pharmaceutically acceptable salt or solvate of them;    -   16) A pharmaceutical composition, which comprises the compound        according to any one of above 13) to 15), a prodrug thereof, a        pharmaceutically acceptable salt or solvate of them, together        with a pharmaceutically acceptable additive;    -   17) The pharmaceutical composition according to above 16), which        is used to enhance the expression of apoAI; and    -   18) The pharmaceutical composition according to above 16), which        is used for prevention and/or treatment of dyslipidemia or        arteriosclerotic diseases.

Further, the invention provides a method of enhancing the expression ofapoAI, and a method of prevention or treatment of dyslipidemia orarteriosclerotic diseases, both of which comprises administrating atherapeutically effective amount of a compound of formula (II) asdescribed above: a prodrug thereof, a pharmaceutically acceptable saltor solvate of them.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine.

The term “lower alkyl” as used herein refers to a straight or branchedchain alkyl comprising 1 to 6 carbon atoms, preferably 1 to 3 carbonatoms. Examples of the lower alkyl include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, hexyl, isohexyl, and the like.

The term “lower alkyl that may be optionally substituted” as used hereinincludes a lower alkyl, of which any position may be substituted by oneor more substituents. The substituent includes a halogen, a hydroxy, alower alkoxy, a monocyclic or bicyclic carbocyclic group, an acyl, anacyloxy, a carboxy, a lower alkoxycarbonyl, an amino, a loweralkylamino, a nitro, a monocyclic or bicyclic heterocyclic group, andthe like.

Alkyl moiety of “lower alkoxy”, “lower alkylthio” or “lower alkylamino”is similar to the “lower alkyl” as described above.

The term “alkylenedioxy” specifically includes methylenedioxy,ethylenedioxy, and the like.

Lower alkyl moiety of “lower alkoxycarbonyl” is similar to the “loweralkyl” as described above, and substituent of “lower alkoxycarbonyl thatmay be optionally substituted” is similar to the substituent of “loweralkyl that may be optionally substituted” as described above.

The term “acyl” includes an aroyl and an aliphatic acyl containing 1 to7 carbon atoms. Here, “aroyl” refers to an aromatic acyl group formed bydeleting a hydroxy from an aromatic carbocyclic acid. Examples of theacyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valery,pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, andbenzoyl.

Acyl moiety of “acyloxy” is similar to the “acyl”.

The term “monocyclic carbocyclic group” as used herein refers to acyclic ring group containing 3 to 10 carbon atoms, preferably 5 to 8carbon atoms, and includes an aromatic and non-aromatic cyclic ringgroup. Examples of the carbocyclic group include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, cyclononyl, cyclodecyl, and phenyl.

The term “monocyclic heterocyclic group” refers to a cyclic ring groupwherein one or more carbon atoms that are contained in the “monocycliccarbocyclic group” as described above and that can be substituted,is(are) substituted by a hetero atom selected from the group consistingof N, S and O. Examples include aromatic heterocyclic groups such aspyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl,pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and thienyl;and non-aromatic heterocyclic groups such as dioxanyl, dioxazinyl,dioxolanyl, dioxolyl, dithiazinyl, imidazolidinyl, imidazolinyl,morpholyl, oxazinyl, oxadiazyl, furazaryl, oxathianyl, oxathiazinyl,oxathiolanyl, oxazolidinyl, oxazolinyl, piperazinyl, piperidinyl,pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, thiadiazolidinyl, thianyl, thiazinyl, thiadiazinyl,thiiranyl, and thiolanyl. Preferred ones include pyridyl, pyrimidinyl,pyrrolyl, furyl, thienyl, and thiazolyl.

Heterocyclic moiety of “monocyclic aromatic heterocyclic oxy” is similarto the aromatic heterocyclic group as described above.

The term “bicyclic carbocyclic group” refers to an aromatic ornon-aromatic cyclic group containing 6 to 12 carbon atoms wherein twocyclic rings are condensed. Examples include naphthyl, indanyl, indenyl,dihydronaphthyl, and tetrahydronaphthyl, and preferably, naphthyl.

The term “bicyclic heterocyclic group” includes a cyclic ring compoundwherein one or more carbon atoms that are contained in the “bicycliccarbocyclic group” as described above and that can be substituted,is(are) substituted by a hetero atom selected from the group consistingof N, S and O. Examples include indolyl, isoindolyl, indolizinyl,benzimidazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl,benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl,benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopiridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl,purinyl, pteridinyl, naphthylidinyl, and pyrazinopyridazinyl. Preferableexamples include indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl,imidazopyridyl, triazolopyridyl, quinolyl, isoquinolyl, andquinoxalinyl.

The term “aromatic heterocyclic group” refers to only an aromaticheterocyclic group among the groups of “heterocyclic group” as describedabove.

Substituent in “monocyclic or bicyclic carbocyclic group that may beoptionally substituted”, “phenyl that may be optionally substituted”,“naphthyl that may be optionally substituted”, and “monocycliccarbocyclic group that may be optionally substituted” includes ahalogen; a hydroxy; a lower alkyl optionally substituted by a halogen, ahydroxy, or a lower alkoxy; a lower alkoxy optionally substituted by ahalogen, a hydroxy, a carboxy, or a lower alkoxycarbonyl; a loweralkenyl optionally substituted by a halogen or a hydroxy; a loweralkenyloxy optionally substituted by a halogen or a hydroxy; a loweralkylthio; a non-aromatic carbocyclic group optionally substituted by ahalogen, a hydroxy, or a lower alkyl; an acyl; an acyloxy; a carboxy; alower alkoxycarbonyl; a lower alkenyloxycarbonyl; an amino optionallysubstituted by a lower alkyl or an acyl; a hydrazino, a nitro; a cyano;a phenyl or naphthyl optionally substituted by a halogen, a hydroxy, alower alkyl or a lower alkoxy; a heterocyclic group; a phenoxyoptionally substituted by a halogen, a hydroxy, or a lower alkyl; amonocyclic aromatic heterocyclic oxy; an oxo; and an alkylenedioxyoptionally substituted by a lower alkyl, a lower alkoxy, a phenyl or thelike; all of which may be bonded at one or more arbitrary positions.

Preferable examples include a halogen; a hydroxy; a lower alkyloptionally substituted by a halogen or a hydroxy; a lower alkoxyoptionally substituted by a halogen, a hydroxy, a carboxy, or a loweralkoxycarbonyl; a lower alkenyl; a lower alkylthio; an acyl; an acyloxy;a carboxy; a lower alkoxycarbonyl; an amino optionally substituted by alower alkyl or an acyl; a hydrazino, a nitro; a cyano; a phenyl; aheterocyclic group; a phenoxy; and an alkylenedioxy.

Substituent in “monocyclic aromatic heterocyclic group that may beoptionally substituted”, “monocyclic heterocyclic group that may beoptionally substituted”, “monocyclic aromatic heterocyclic group thatmay be optionally substituted”, “monocyclic or bicyclic aromaticheterocyclic group that may be optionally substituted”, “2-pyridyl thatmay be optionally substituted”, “2-pyridyl, 2-quinolyl, 2-quinoxalyl,2-benzisoxazolyl, 2-benzothiazolyl, or 2-benzimidazolyl, each of whichmay be optionally substituted”, and “3-pyridyl, furyl, thienyl,pyrrolyl, or thiazolyl, each of which may be optionally substituted” issimilar to the substituent in “monocyclic or bicyclic carbocyclic groupthat may be optionally substituted” and the like as described above.Preferable examples include a halogen; a hydroxy; a lower alkyloptionally substituted by a lower alkoxy; a lower alkoxy; a loweralkenyl; a lower alkylthio; an acyl; an acyloxy; a carboxy; a loweralkoxycarbonyl; an amino optionally substituted by a lower alkyl; and aphenyl optionally substituted by a lower alkoxy; and a monocyclicheterocyclic group.

The term “a monocyclic or bicyclic aromatic heterocyclic group thatcontains a nitrogen atom at the position adjacent to the constituentatom of the ring that has a binding bond” includes “a monocyclic orbicyclic aromatic heterocyclic group” as described above that has, atortho position with respect to the constituent N atom of a ring, abinding bond to:

Specific examples include monocyclic aromatic heterocyclic groups suchas 2-pyridyl, 2- or 4-pyrimidinyl, 3-pyridazinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 2-pyrrolyl, 1- or 3-pyrazolyl, 2- or 4-imidazolyl,2- or 4-oxazolyl, 3-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,3-thiazol-2-yl,1,3-thiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,3,4-thiadiazol-2-yl, 3-isothiazolyl, 1,2,3-triazol-4-yl,1H-tetrazol-1-yl, and 1H-tetrazol-5-yl; and bicyclic aromaticheterocyclic groups such as 2-benzimidazolyl, 3-benzisothiazolyl,3-benzisoxazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 1-benzotriazolyl, 1-or 3-indazolyl, 3-cinnolinyl, 2-indoyl, 1- or 3-isoindolyl,2-[1.7]-naphthylidinyl, 2-, 4-, 6- or 7-pteridinyl, 2-, 6 or 8-purinyl,1- or 3-isoquinolyl, 2-quinolyl, 2- or 4-quinazolinyl, and2-quinoxalinyl.

The phrase “a monocyclic or bicyclic aromatic heterocyclic group thatmay be optionally substituted, and that contains a nitrogen atom at theposition adjacent to the constituent atom of the ring that has a bindingbond” means that one or more substituents may be bonded at arbitrarypositions, similarly to “monocyclic or bicyclic carbocyclic group thatmay be optionally substituted” as described above.

The term “linker group comprising 1 to 2 atoms” refers to a groupwherein the number of the atom (except for hydrogen atom) comprised in alinker group is 1 or 2, includes a linker formed by 1 or 2 groups thatare arbitrarily selected from a group consisting of —CR¹R²—, —O—, —NR³—,and —S—. The bond between the two groups may be a double bond, ifpossible. Examples include linker groups comprising 1 to 2 atoms such as—CR¹R²—, —O—, —NR³—, —S—, —(CR¹R²)₂—, —CR¹R²O—, —CR¹R²NR³—, —CR¹R²S—,—OCR¹R²—, —NR³CR¹R²—, —SCR¹R²—, —CR¹═CR¹—, —CR¹═N—, —N═CR¹—, and —N═N—wherein R¹, R² and R³ are independently a hydrogen, a halogen, ahydroxy, a lower alkyl, a lower alkoxy, or an amino, or R¹ and R² may becombined together to form an oxo, and two R¹s or more and two R²s ormore each may be different one another. Preferable examples include alinker wherein R¹, R² and R³ are a hydrogen, and more preferable onesinclude —S—, —O—, —NR³—, —CR¹═CR¹—, —CR¹═N—, and —N═CR¹—.

The phrase “Ar² that are bonded to Z¹ via the two atoms” means that Ar²and Z¹ have a relationship as shown below:

Alternatively, the phrase “Ar¹ that are bonded to Z² via the two atoms”in case that m is 1, and X is a group of formula (α) means that Ar¹ andZ² have a relationship as shown below:

The phrase “Z¹ and Z² may be independently a linker group comprising 1to 2 atoms that may combine with the constituent atoms of the rings Ar²and Ar¹ - - - to form a condensed ring” means that Z¹ or Z², that isused as a constituent atom of a ring, is combined with Ar² and/or Ar¹ toform a condensed ring. Specifically, the phrase means the followinggroup is formed:

wherein the atoms as indicated by W¹ and W² may be either a carbon atomor a nitrogen atom. Examples of the condensed cyclic ring group formedaccording to the definition include 2-naphthyl, 2-, 5- or 6-benzofuryl,2-, 5- or 6-benzimidazolyl, 2-, 5- or 6-benzothiazolyl,5-benzisothiazoryl, 5- or 6-benzisoxazolyl, 2-, 5- or 6-benzoxazolyl,5-benzotriazolyl, 5- or 6-benzoxadiazolyl, 2-, 5- or 6-benzothienyl, 3-,5- or 6-cinnolinyl, 5- or 6-indazolyl, 2-, 5- or 6-indolyl,5-isoindolyl, 3-, 6- or 7-isoquinolyl, 2- or 6-quinazolinyl, 2-, 3-, 6-or 7-quinolyl, 2- or 6-quinoxalinyl, 3-, 6- or 7-1H-isochromenyl, 3-, 6-or 7-2H-chromenyl, 3-thiochromenyl, 3-, 6- or 7-1,2-dihydroquinolinyl,2- or 3-[1,7]naphthylidinyl, and 6-phthalazinyl.

The compounds according to the invention include pharmaceuticallyacceptable, producible salts. Examples of the “pharmaceuticallyacceptable salts” include a salt with an inorganic acid e.g. those withhydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or thelike; a salt with an organic acid e.g. those with p-toluenesulfonicacid, methanesulfonic acid, oxalic acid, citric acid, or the like; asalt with an organic base e.g. ammonium, trimethylammonium,triethylammonium, or the like; a salt with an alkaline metal e.g. sodiumor potassium, or the like; a quaternary salt with alkyl halide e.g.,methyl iodide, ethyl iodide or the like; and a salt with an alkalineearth metal e.g., calcium or magnesium, or the like.

The compounds according to the invention may form solvates ascoordinated with a suitable organic solvent and/or water. Hydrates areexemplified.

The compounds according to the invention also include prodrugs. In thecontext of the invention, a “prodrug” is a derivative of a compoundaccording to the invention comprising a chemically or metabolicallycleavable group. In the course of metabolism in the body, a prodrugshows a pharmacological activity as a result of conversion to thecompounds according to the invention. Method for selecting and producingsuitable prodrug derivatives are described in, e.g. “Design of Prodrugs,Elsevier, Amsterdam (1985)”.

Prodrugs of compound (I) according to the invention having a carboxy areexemplified by an ester derivative prepared by condensing the carboxygroup of compound (I) with a suitable alcohol, and alternatively by anamide derivative prepared by reacting the carboxy group of compound (I)and a suitable amine.

Prodrugs of compound (I) according to the invention having a hydroxy areexemplified by an acyloxy derivative prepared by reacting the hydroxygroup of compound (I) and a suitable acyl halide or a suitable acidanhydride.

Prodrugs of compound (I) according to the invention having an amino areexemplified by an amide derivative prepared by reacting the amino groupof compound (I) and a suitable acid halide or a suitable mixed anhydridecompound.

When compound (I) according to the invention has asymmetric carbonatom(s), then the invention encompasses a racemic mixture, both ofenantiomers, and all of diastereomers. When compound (I) according tothe invention has a double bond, the invention include both of geometricisomers resulting from possible arrangements of its substituents.

Although all of the compounds according to the invention have anactivity for enhancing the expression of apoAI, the following compoundscan be listed as preferable compounds.

In formula (I):

-   -   a compound wherein Ar¹ is a phenyl or naphthyl that may be        optionally substituted wherein the substituent is a halogen; a        lower alkyl optionally substituted by a halogen; a hydroxy; a        lower alkoxy; an aryloxy; an acyloxy; a carboxy; a lower        alkoxycarbonyl; an amino optionally substituted by a lower alkyl        or a lower acyl; a phenyl; a nitro; a lower alkylthio; a cyano;        a monocyclic heterocyclic group; or an alkylenedioxy        (hereinafter, regarded as Ar1-a);    -   a compound wherein Ar¹ is an unsubstituted phenyl or an        unsubstituted naphthyl (hereinafter, regarded as Ar1-b);    -   a compound wherein Ar¹ is a monocyclic or bicyclic aromatic        heterocyclic group that may be optionally substituted        (hereinafter, regarded as Ar1-c);    -   a compound wherein Ar¹ is a monocyclic or bicyclic aromatic        heterocyclic group that may be optionally substituted wherein        the substituent is a lower alkyl or an amino (hereinafter,        regarded as Ar1-d);    -   a compound wherein Ar¹ is a monocyclic or bicyclic heterocyclic        group that contains a nitrogen at the ortho position, and that        may be optionally substituted (hereinafter, regarded as Ar1-e);    -   a compound wherein Ar¹ is a monocyclic or bicyclic heterocyclic        group that contains a nitrogen at the ortho position, and that        may be optionally substituted wherein the substituent is a lower        alkyl or an amino (hereinafter, regarded as Ar1-f);    -   a compound wherein Ar¹ is 2-quinolyl, 2-quinoxalyl,        2-benzimidazolyl, 2-thiazolyl, 2-benzothiazolyl, 2-oxazolyl,        2-benzoxazolyl, 2-oxadiazolyl, 2-pyridyl, 2-pyrimidyl, or        2-imidazolyl (hereinafter, regarded as Ar1-g);    -   a compound wherein m is 0, and n is 1 (hereinafter, regarded as        X-a);    -   a compound wherein m is 0, and n is 2 (hereinafter, regarded as        X-b);    -   a compound wherein m is 1, n is 0, X is a group of formula (α),        and Q is —N═ (hereinafter, regarded as X-c);    -   a compound wherein m and n are 1, X is a group of formula (α),        and Q is —CH₂— or —N═ (hereinafter, regarded as X-d);    -   a compound wherein m is 1, n is 2, X is a group of formula (α),        and Q is —CH═ (hereinafter, regarded as X-e);    -   a compound wherein m and n are 1, X is CH₂CH₂ or S (hereinafter,        regarded as X-f);    -   a compound wherein Y¹ and Z¹ are a hydrogen (hereinafter,        regarded as YZ-a);    -   a compound wherein Y¹ and Z¹ are independently a hydrogen, a        halogen, a lower alkyl, or a cyano (hereinafter, regarded as        YZ-b);    -   a compound wherein Y¹ is a hydrogen, and Z¹ is a linker group        comprising 1 to 2 atoms (hereinafter, regarded as YZ-c);    -   a compound wherein Ar² is a phenyl or naphthyl that may be        optionally substituted wherein the substituent is a halogen; a        lower alkyl optionally substituted by a halogen; a hydroxy; a        lower alkoxy; an aryloxy; an acyloxy; a carboxy; a lower        alkoxycarbonyl; an amino optionally substituted by a lower alkyl        or a lower acyl; a phenyl; a nitro; a lower alkylthio; a cyano;        a monocyclic heterocyclic group; or a lower alkylenedioxy        (hereinafter, regarded as Ar2-a);    -   a compound wherein Ar² is a monocyclic or bicyclic aromatic        heterocyclic group that may be optionally substituted        (hereinafter, regarded as Ar2-b);    -   a compound wherein Ar² is a monocyclic or bicyclic aromatic        heterocyclic group that may be optionally substituted wherein        the substituent is a lower alkyl, a lower alkoxy, a lower alkoxy        (a lower alkyl), a halogen, a lower alkoxycarbonyl, a phenyl, a        lower alkoxyphenyl, or a monocyclic heterocyclic group        (hereinafter, regarded as Ar2-c);    -   a compound wherein Ar² is furyl, thiazolyl, or a pyrrolyl,        thienyl, imidazolyl or pyridyl, each of which may be optionally        substituted (hereinafter, regarded as Ar2-d);    -   a compound wherein a combination of Ar¹; m, n, and X; and Y¹ and        Z¹; Ar² (Ar1, X, YZ, Ar2) is any one of the followings: (Ar1, X,        YZ, Ar2)=(Ar1-a, X-a, YZ-a, Ar2-b), (Ar1-a, X-a, YZ-a, Ar2-d),        (Ar1-b, X-a, YZ-a, Ar2-b), (Ar1-b, X-a, YZ-a, Ar2-d), (Ar1-c,        X-a, YZ-a, Ar2-a), (Ar1-c, X-a, YZ-a, Ar2-b), (Ar1-c, X-a, YZ-a,        Ar2-c), (Ar1-c, X-a, YZ-a, Ar2-d), (Ar1-e, X-a, YZ-a, Ar2-a),        (Ar1-e, X-a, YZ-a, Ar2-b), (Ar1-e, X-a, YZ-a, Ar2-c), (Ar1-e,        X-a, YZ-a, Ar2-d), (Ar1-g, X-a, YZ-a, Ar2-a), (Ar1-g, X-a, YZ-a,        Ar2-b), (Ar1-g, X-a, YZ-a, Ar2-c), (Ar1-g, X-a, YZ-a, Ar2-d),        (Ar1-c, X-a, YZ-b, Ar2-b), (Ar1-c, X-a, YZ-b, Ar2-d), (Ar1-e,        X-a, YZ-b, Ar2-b), (Ar1-e, X-a, YZ-b, Ar2-d), (Ar1-g, X-a, YZ-b,        Ar2-b), (Ar1-g, X-a, YZ-b, Ar2-d), (Ar1-b, X-a, YZ-c, Ar2-a),        (Ar1-c, X-a, YZ-c, Ar2-a), (Ar1-a, X-b, YZ-a, Ar2-b), (Ar1-a,        X-b, YZ-a, Ar2-d), (Ar1-b, X-b, YZ-a, Ar2-b), (Ar1-b, X-b, YZ-a,        Ar2-d), (Ar1-c, X-b, YZ-a, Ar2-a), (Ar1-c, X-b, YZ-a, Ar2-b),        (Ar1-c, X-b, YZ-a, Ar2-c), (Ar1-c, X-b, YZ-a, Ar2-d), (Ar1-e,        X-b, YZ-a, Ar2-a), (Ar1-e, X-b, YZ-a, Ar2-b), (Ar1-e, X-b, YZ-a,        Ar2-c), (Ar1-e, X-b, YZ-a, Ar2-d), (Ar1-g, X-b, YZ-a, Ar2-a),        (Ar1-g, X-b, YZ-a, Ar2-b), (Ar1-g, X-b, YZ-a, Ar2-c), (Ar1-g,        X-b, YZ-a, Ar2-d), (Ar1-b, X-b, YZ-b, Ar2-b), (Ar1-c, X-b, YZ-b,        Ar2-a), (Ar1-c, X-b, YZ-b, Ar2-b), (Ar1-c, X-b, YZ-b, Ar2-d),        (Ar1-c, X-b, YZ-c, Ar2-a), (Ar1-c, X-b, YZ-c, Ar2-b), (Ar1-c,        X-b, YZ-c, Ar2-d), (Ar1-e, X-b, YZ-c, Ar2-a), (Ar1-e, X-b, YZ-c,        Ar2-d), (Ar1-g, X-b, YZ-c, Ar2-a), (Ar1-g, X-b, YZ-c, Ar2-d),        (Ar1-b, X-c, YZ-c, Ar2-a), (Ar1-b, X-c, YZ-c, Ar2-b), (Ar1-b,        X-c, YZ-c, Ar2-d), (Ar1-b, X-d, YZ-c, Ar2-a), (Ar1-b, X-d, YZ-c,        Ar2-b), (Ar1-b, X-d, YZ-c, Ar2-d), (Ar1-c, X-e, YZ-a, Ar2-b),        (Ar1-c, X-e, YZ-a, Ar2-d), (Ar1-e, X-e, YZ-a, Ar2-b), (Ar1-e,        X-e, YZ-a, Ar2-d), (Ar1-g, X-e, YZ-a, Ar2-b), (Ar1-g, X-e, YZ-a,        Ar2-d), (Ar1-c, X-e, YZ-b, Ar2-b), (Ar1-c, X-e, YZ-b, Ar2-d),        (Ar1-e, X-e, YZ-b, Ar2-b), (Ar1-e, X-e, YZ-b, Ar2-d), (Ar1-g,        X-e, YZ-b, Ar2-b), (Ar1-g, X-e, YZ-b, Ar2-d), (Ar1-b, X-f, YZ-a,        Ar2-b), (Ar1-b, X-f, YZ-a, Ar2-d), (Ar1-c, X-f, YZ-a, Ar2-a),        (Ar1-e, X-f, YZ-a, Ar2-a), (Ar1-g, X-f, YZ-a, Ar2-a).    -   (Ar1-c, X-e, YZ-c, Ar2-a), (Ar1-c, X-e, YZ-c, Ar2-b), (Ar1-c,        X-e, YZ-c, Ar2-d), (Ar1-e, X-e, YZ-c, Ar2-a), (Ar1-e, X-e, YZ-c,        Ar2-b), (Ar1-e, X-e, YZ-c, Ar2-d), (Ar1-g, X-e, YZ-c, Ar2-a),        (Ar1-g, X-e, YZ-c, Ar2-b), and (Ar1-g, X-e, YZ-c, Ar2-d); and a        prodrug thereof, a pharmaceutically acceptable salt or solvate        of them.

Specific compounds are exemplified by the followings:

-   2-phenylquinoxaline (Ia-1)-   2-(4-chlorophenyl)quinoxaline (Ia-2)-   2-(4-methoxyphenyl)quinoxaline (Ia-3)-   2-(pyridin-3-yl)quinoxaline (Ia-4)-   2-(pyridin-3-yl)quinoxaline (Ia-5)-   2-(thiophen-3-yl)quinoxaline (Ia-6)-   2-(furan-3-yl)quinoxaline (Ia-7)-   2-(pyrrol-3-yl)quinoxaline (Ia-8)-   2-(thiophen-2-yl)quinoxaline (Ia-9)-   2-(biphenyl-4-yl)quinoxaline (Ia-10)-   2-(naphthalen-2-yl)quinoxaline (Ia-11)-   2-(biphenyl-4-yl)quinoline (Ia-12)-   2-phenylquinoline (Ia-13)-   2-(4-methoxyphenyl)quinoline (Ia-14)-   2-(thiophen-3-yl)quinoline (Ia-15)-   2-(4-chlorophenyl)quinoline (Ia-16)-   2-biphenyl-4-yl-4-methyl-quinoline (Ia-17)-   3-phenylquinoline (Ia-18)-   2-(4-methoxyphenyl)-1H-benzimidazole (Ia-19)-   2-phenylbenzothiazole (Ia-20)-   [2,2′]bibenzothiazolyl (Ia-21)-   2-(4-methoxyphenyl)benzoxazole (Ia-22)-   2-styrylpyridine (Ib-1)-   2-(2-p-tolylvinyl)pyridine (Ib-2)-   methyl 4-(2-pyridin-2-yl-vinyl)-benzoate (Ib-3)-   4-(2-pyridin-2-yl-vinyl)-benzoic acid (Ib-4)-   4-(2-pyridin-2-yl-vinyl) benzonitrile (Ib-5)-   2-(2-biphenyl-4-yl-vinyl)pyridine (Ib-6)-   2-[2-(4-fluorophenyl)vinyl]pyridine (Ib-7)-   N-[4-(2-pyridin-2-yl-vinyl)phenyl]acetamide methyl iodide (Ib-8)-   2-[2-(4-trifluorophenyl)vinyl]pyridine (Ib-9)-   2-[2-(2-hydroxyphenyl)vinyl]pyridine (Ib-11)-   2-[2-(4-methoxyphenyl)vinyl]pyridine (Ib-12)-   2-(2-benzo[1,3]dioxol-5-yl-vinyl)pyridine (Ib-13)-   2-[2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)vinyl]pyridine (Ib-14)-   2-(2-naphthalen-2-yl-vinyl)pyridine (Ib-17)-   6-(2-pyridin-2-yl-vinyl)quinoline (Ib-19)-   6-(2-pyridin-2-yl-vinyl)-1H-indole (Ib-20)-   2-(2-benzofuran-5-yl-vinyl)pyridine (Ib-21)-   2-(2-benzofuran-6-yl-vinyl)pyridine (Ib-22)-   5-(2-pyridin-2-yl-vinyl)-1H-indole (Ib-23)-   2-(2-benzothiophen-5-yl-vinyl)pyridine (Ib-24)-   5-(2-pyridin-2-yl-vinyl)benzo[1,2,5]thiadiazole (Ib-25)-   5-(2-pyridin-2-yl-vinyl)benzo[1,2,5]oxadiazole (Ib-26)-   7-(2-pyridin-2-yl-vinyl)imidazo[1,2-a]pyridine (Ib-27)-   7-(2-pyridin-2-yl-vinyl)-[1,2,4]triazolo[1,5-a]pyridine (Ib-28)-   6-(2-pyridin-2-yl-vinyl)imidazo[1,2-a]pyridine (Ib-29)-   3-(2-pyridin-2-yl-vinyl)quinoline (Ib-30)-   5-(2-pyridin-2-yl-vinyl)benzothiazole (Ib-31)-   6-(2-pyridin-2-yl-vinyl)-[1,2,4]triazolo[1,5-a]pyridine (Ib-32)-   2-(2-benzofuran-2-yl-vinyl)pyridine (Ib-33)-   2-(2-pyridin-2-yl-vinyl)benzothiazole (Ib-34)-   2-(2-benzofuran-3-yl-vinyl)pyridine (Ib-35)-   1-methyl-2-(2-pyridin-2-yl-vinyl)-1H-indole (Ib-36)-   2-(2-pyridin-2-yl-vinyl)-1H-indole (Ib-37)-   2-(2-pyridin-2-yl-vinyl)-1H-benzimidazole (Ib-38)-   2-(2-benzo[b]thiophen-2-yl-vinyl)pyridine (Ib-39)-   6-(2-pyridin-2-yl-vinyl)quinoxaline (Ib-40)-   1,2-bis-(2-pyridyl)ethylene (Ib-41)-   1-(2-pyridyl)-2-(3-pyridyl)ethylene (Ib-43)-   1-(2-pyridyl)-2-(4-pyridyl)ethylene (Ib-45)-   2-[2-(1-methyl-1H-pyrrol-2-yl)vinyl]pyridine (Ib-50)-   2-(2-thiophen-3-yl-vinyl)pyridine (Ib-52)-   2-styrylquinoxaline (Ib-56)-   2-(2-p-tolylvinyl)quinoxaline (Ib-57)-   methyl 4-(2-quinoxaline-2-yl-vinyl)-benzoate (Ib-58)-   4-(2-quinoxaline-2-yl-vinyl)-benzoic acid (Ib-59)-   4-(2-quinoxaline-2-yl-vinyl)benzonitrile (Ib-60)-   2-(2-biphenyl-4-yl-vinyl)quinoxaline (Ib-61)-   2-(2-naphthalen-2-yl-vinyl)quinoxaline (Ib-62)-   2-(2-benzothiophen-6-yl-vinyl)quinoxaline (Ib-63)-   2-[2-(4-fluorophenyl)vinyl]quinoxaline (Ib-64)-   2-[2-(4-chlorophenyl)vinyl]quinoxaline (Ib-65)-   2-[2-(4-bromophenyl)vinyl]quinoxaline (Ib-66)-   2-[2-(4-methoxyphenyl)vinyl]quinoxaline (Ib-67)-   4-(2-quinoxaline-2-yl-vinyl)phenol (Ib-68)-   4-(2-quinoxaline-2-yl-vinyl)phenylamine (Ib-69)-   N-[4-(2-quinoxaline-2-yl-vinyl)phenyl]acetamide (Ib-70)-   2-[2-(4-dimethylaminophenyl) vinyl]quinoxaline (Ib-71)-   2-[2-(4-phenoxyphenyl)vinyl]quinoxaline (Ib-72)-   2-(2-furan-2-yl-vinyl)quinoxaline (Ib-73)-   2-(2-furan-3-yl-vinyl)quinoxaline (Ib-75)-   2-(2-thiazol-5-yl-vinyl)quinoxaline (Ib-76)-   2-(2-thiophen-3-yl-vinyl)quinoxaline (Ib-77)-   2-[2-(1H-pyrrol-3-yl)vinyl]quinoxaline (Ib-78)-   2-[2-(1H-[1,2,3]triazol-4-yl)vinyl]quinoxaline (Ib-79)-   [4-(2-benzoxazole-2-yl-vinyl)phenyl]dimethylamine (Ib-80)-   2-(2-p-tolyl-vinyl)benzoxazole (Ib-81)-   4-(2-benzoxazole-2-yl-vinyl)-benzoic acid (Ib-82)-   2-[2-(1-methyl-1H-pyrrol-2-yl)vinyl]benzoxazole (Ib-83)-   2-(2-pyridin-2-yl-vinyl)benzoxazole (Ib-84)-   [4-(2-benzothiazole-2-yl-vinyl)phenyl]dimethylamine (Ib-85)-   4-(2-benzothiazole-2-yl-vinyl)benzonitrile (Ib-86)-   2-(2-thiophen-3-yl-vinyl)benzothiazole (Ib-87)-   ethyl 4-[3-(2-quinoline-2-yl-vinyl)phenoxy]butanoate (Ib-88)-   4-[3-(2-quinoline-2-yl-vinyl)phenoxy]butanoic acid (Ib-89)-   2-[2-(4-methoxyphenyl)vinyl]quinoline (Ib-90)-   2-(2-thiophen-3-yl-vinyl)benzothiazole (Ib-91)-   2-(2-furan-3-yl-vinyl)benzothiazole (Ib-92)-   2-(2-1H-pyrrol-3-yl-vinyl)benzothiazole (Ib-93)-   2-{2-[4-(1H-pyrrol-2-yloxy)phenyl]vinyl}quinoline (Ib-94)-   2-(2-thiophen-3-yl-vinyl)-1H-benzimidazole (Ib-95)-   2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazole (Ib-96)-   2-[2-(4-methoxyphenyl)vinyl]-1H-benzimidazole (Ib-97)-   2-[2-(1H-imidazol-4-yl)vinyl]-1H-benzimidazole (Ib-98)-   ethyl 2-[2-(1H-benzimidazole-2-yl)vinyl]oxazol-4-carboxylate (Ib-99)-   2-(2-thiophen-2-yl-vinyl)pyridine (Ib-100)-   2-pyridin-2-yl-3-thiophen-2-yl-acrylonitrile (Ib-101)-   3-[2-(5-phenyl)-[1,3,4]oxadiazol-2-yl-vinyl]pyridine (Ib-102)-   3-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]vinyl}pyridine    (Ib-103)-   2-(4-phenyl-buta-1,3-dienyl)pyridine (Ic-1)-   2-(4-o-tolyl-buta-1,3-dienyl)pyridine (Ic-2)-   2-[4-(2,5-dimethylphenyl)buta-1,3-dienyl]pyridine (Ic-3)-   2-(4-m-tolyl-buta-1,3-dienyl)pyridine (Ic-4)-   2-[4-(3,5-dimethylphenyl)buta-1,3-dienyl]pyridine (Ic-5)-   2-(4-p-tolyl-buta-1,3-dienyl)pyridine (Ic-6)-   2-[4-(3,4-dimethylphenyl)buta-1,3-dienyl]pyridine (Ic-7)-   2-[4-(2,4,6-trimethylphenyl)buta-1,3-dienyl]pyridine (Ic-8)-   2-[4-(4-trifluoromethylphenyl)buta-1,3-dienyl]pyridine (Ic-9)-   2-[4-(3-trifluoromethylphenyl)buta-1,3-dienyl]pyridine (Ic-10)-   2-[4-(4-methoxyphenyl)buta-1,3-dienyl]pyridine (Ic-11)-   2-[4-(3-methoxyphenyl)buta-1,3-dienyl]pyridine (Ic-12)-   2-[4-(3,4-dimethoxyphenyl)buta-1,3-dienyl]pyridine (Ic-13)-   2-[4-(3,4,5-trimethoxyphenyl)buta-1,3-dienyl]pyridine (Ic-14)-   2-[4-(4-methoxy-3-methylphenyl)buta-1,3-dienyl]pyridine (Ic-15)-   2-[4-(4-methoxy-2,5-dimethylphenyl)buta-1,3-dienyl]pyridine (Ic-16)-   2,6-dimethyl-4-(4-pyridin-2-yl-buta-1,3-dienyl)phenol (Ic-17)-   phenyl 2-methoxy-4-(4-pyridin-2-yl-buta-1,3-dienyl)acetate (Ic-18)-   2-methoxy-4-(4-pyridin-2-yl-buta-1,3-dienyl)phenol (Ic-19)-   2-(4-benzo[1,3]dioxol-5-yl-buta-1,3-dienyl)pyridine (Ic-20)-   2-[4-(7-methylbenzo[1,3]dioxole)-5-yl-buta-1,3-dienyl]pyridine    (Ic-21)-   2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)buta-1,3-dienyl]pyridine    (Ic-22)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)benzo[1,2,5]thiadiazole (Ic-23)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)benzo[1,2,5]oxadiazole (Ic-24)-   7-(4-pyridin-2-yl-buta-1,3-dienyl)imidazo[1,2-a]pyridine (Ic-25)-   7-(4-pyridin-2-yl-buta-1,3-dienyl)-[1,2,4]triazolo[1,5-a]pyridine    (Ic-26)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)-1,3a,7a-triazaindene (Ic-27)-   6-(4-pyridin-2-yl-buta-1,3-dienyl)-[1,2,4]triazolo[1,5-a]pyridine    (Ic-28)-   6-(4-pyridin-2-yl-buta-1,3-dienyl)-1H-indole (Ic-29)-   6-(4-pyridin-2-yl-buta-1,3-dienyl)-1H-benzimidazole (Ic-30)-   2-(4-naphthalen-2-yl-buta-1,3-dienyl)pyridine (Ic-31)-   3-(4-pyridin-2-yl-buta-1,3-dienyl)quinoline (Ic-32)-   6-(4-pyridin-2-yl-buta-1,3-dienyl)quinoline (Ic-33)-   2-(4-benzofuran-5-yl-buta-1,3-dienyl)pyridine (Ic-34)-   2-(4-benzofuran-6-yl-buta-1,3-dienyl)pyridine (Ic-35)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)-1H-indole (Ic-36)-   2-(4-benzo[b]thiophen-5-yl-buta-1,3-dienyl)pyridine (Ic-37)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)benzothiazole (Ic-38)-   2-[4-(2-nitrophenyl)buta-1,3-dienyl]pyridine (Ic-39)-   2-[4-(4-nitrophenyl)buta-1,3-dienyl]pyridine (Ic-40)-   2-[4-(4-fluorophenyl)buta-1,3-dienyl]pyridine (Ic-41)-   2-[4-(4-chlorophenyl)buta-1,3-dienyl]pyridine (Ic-42)-   2-[4-(3-fluorophenyl)buta-1,3-dienyl]pyridine (Ic-43)-   2-[4-(4-methylsulfanilphenyl)buta-1,3-dienyl]pyridine (Ic-44)-   N-[4-(4-pyridin-2-yl-buta-1,3-dienyl)phenyl]acetamide (Ic-45)-   dimethyl-[4-(4-pyridin-2-yl-buta-1,3-dienyl)phenyl]amine (Ic-46)-   1,4-bis-(2-pyridyl)-1,3-butadiene (Ic-48)-   2-(4-pyridin-2-yl-buta-1,3-dienyl)quinoline (Ic-49)-   1-(2-pyridyl)-4-(2-methylpyridin-6-yl)-1,3-butadiene (Ic-50)-   1-(2-pyridyl)-4-(5-methylpyridin-2-yl)-1,3-butadiene (Ic-51)-   1-(2-pyridyl)-4-(5-methoxypyridin-2-yl)-1,3-butadiene (Ic-52)-   1-(2-pyridyl)-4-(4-methoxypyridin-2-yl)-1,3-butadiene (Ic-53)-   1-(3-pyridyl)-4-(2-pyridyl)-1,3-butadiene (Ic-54)-   1-(2-pyridyl)-4-(2-thiophen-2-yl-pyridin-5-yl)-1,3-butadiene (Ic-55)-   1-(2-pyridyl)-4-(2-methylpyridin-5-yl)-1,3-butadiene (Ic-56)-   1-(2-pyridyl)-4-(2-methoxypyridin-5-yl)-1,3-butadiene (Ic-57)-   1-(2-pyridyl)-4-(2-chloropyridin-5-yl)-1,3-butadiene (Ic-58)-   1-(2-pyridyl)-4-(4-pyridyl)-1,3-butadiene (Ic-59)-   1-(2-pyridyl)-4-(2-chloropyridin-4-yl)-1,3-butadiene (Ic-60)-   1-(2-pyridyl)-4-(2-methoxypyridin-4-yl)-1,3-butadiene (Ic-61)-   1-(2-pyridyl)-4-(2-methylpyridin-4-yl)-1,3-butadiene (Ic-62)-   5-(4-pyridin-2-yl-buta-1,3-dienyl)pyrimidine (Ic-63)-   2-(4-pyridin-2-yl-buta-1,3-dienyl)-[1,3,5]triazine (Ic-64)-   4-(4-pyridin-2-yl-buta-1,3-dienyl)pyrimidine (Ic-65)-   2-(4-phenyl-buta-1,3-dienyl)quinoxaline (Ic-68)-   2-(4-phenyl-buta-1,3-dienyl)quinoline (Ic-69)-   3-(4-pyridin-3-yl-buta-1,3-dienyl)isoquinoline (Ic-70)-   2-(3-methyl-4-phenyl-buta-1,3-dienyl)pyridine (Ic-71)-   2-(3-pentyl-4-phenyl-buta-1,3-dienyl)pyridine (Ic-72)-   2-(3-bromo-4-phenyl-buta-1,3-dienyl)pyridine (Ic-73)-   2-(4-phenyl-penta-1,3-dienyl)pyridine (Ic-75)-   2-phenyl-5-pyridin-2-yl-penta-2,4-diene nitrile (Ic-76)-   5-phenyl-2-pyridin-2-yl-penta-2,4-diene nitrile (Ic-77)-   2-(4-furan-2-yl-buta-1,3-dienyl)pyridine (Ic-78)-   2-(4-furan-3-yl-buta-1,3-dienyl)pyridine (Ic-79)-   2-(4-furan-3-yl-buta-1,3-dienyl)pyridine hydrochloride (Ic-80)-   2-(4-thiophen-2-yl-buta-1,3-dienyl)pyridine (Ic-81)-   2-(4-thiophen-3-yl-buta-1,3-dienyl)pyridine (Ic-82)-   2-[4-(3-methylthiophen-2-yl)buta-1,3-dienyl]pyridine (Ic-83)-   2-(4-thiazol-2-yl-buta-1,3-dienyl)pyridine (Ic-84)-   2-[4-(5-methyl-3H-imidazol-4-yl)buta-1,3-dienyl]pyridine (Ic-85)-   2-(4-isoxazol-4-yl-buta-1,3-dienyl)pyridine (Ic-86)-   2-(4-isoxazol-3-yl-buta-1,3-dienyl)pyridine (Ic-87)-   2-(4-oxazol-4-yl-buta-1,3-dienyl)pyridine (Ic-88)-   2-[4-(1H-pyrazol-3-yl)buta-1,3-dienyl]pyridine (Ic-89)-   2-[4-(1H-pyrrol-3-yl)buta-1,3-dienyl]pyridine (Ic-90)-   2-[4-(1H-1,2,4-triazol-3-yl)buta-1,3-dienyl]pyridine (Ic-91)-   2-(6-furan-3-yl-hexa-1,3,5-trienyl)pyridine (Ic-93)-   2-(6-furan-2-yl-hexa-1,3,5-trienyl)pyridine (Ic-94)-   2-(6-thiophen-3-yl-hexa-1,3,5-trienyl)pyridine (Ic-95)-   2-(6-phenyl-hexa-1,3,5-trienyl)pyridine (Ic-96)-   1,6-bis-(2-pyridyl)-1,3,5-hexatriene (Ic-97)-   1-(2-pyridyl)-6-(3-pyridyl)-1,3,5-hexatriene (Ic-98)-   1-(2-pyridyl)-6-(4-pyridyl)-1,3,5-hexatriene (Ic-102)-   2-(6-thiazol-4-yl-hexa-1,3,5-trienyl)pyridine (Ic-103)-   2-(6-thiophen-3-yl-hexa-1,3,5-trienyl)pyridine (Ic-104)-   2-(6-isoxazol-4-yl-hexa-1,3,5-trienyl)pyridine (Ic-105)-   2-(6-isoxazol-3-yl-hexa-1,3,5-trienyl)pyridine (Ic-106)-   2-(6-oxazol-4-yl-hexa-1,3,5-trienyl)pyridine (Ic-107)-   2-[6-(1H-pyrazol-3-yl)hexa-1,3,5-trienyl]pyridine (Ic-108)-   2-[2-(2H-chromen-3-yl)vinyl]pyridine (Ic-110)-   2-(4-phenyl-but-1-enyl)pyridine (Id-2)-   2-styrylsulfanil-pyridine (Id-4)-   pyridin-2-yl-styrylamine (Id-5), and-   (3-phenylallylidene)pyridin-2-yl-amine (Id-6).

Among them, more preferable compounds are as follows:

-   -   Ia-1, Ia-2, Ia-3, Ia-6, Ia-10, Ia-12, Ia-13, Ia-14, Ia-15,        Ia-16, Ia,-17, Ia-18, Ia-19, Ia-20, Ia-21, Ia-22. Ib-1, Ib-9,        Ib-11, Ib-17, Ib-20, Ib-33, Ib-34, Ib-35, Ib-50, Ib-52, Ib-56,        Ib-57, Ib-58, Ib-59, Ib-60, Ib-61, Ib-64, Ib-65, Ib-66, Ib-67,        Ib-68, Ib-69, Ib-70, Ib-72, Ib-73, Ib-75, Ib-77, Ib-84, Ib-85,        Ib-87, Ib-88, Ib-89, Ib-91, Ib-100, Ib-101, Ib-102, Ic-1, Ic-2,        Ic-4, Ic-6, Ic-9, Ic-11, Ic-15, Ic-18, Ic-19, Ic-39, Ic-40,        Ic-41, Ic-44, Ic-45, Ic-46, Ic-48, Ic-54, Ic-59, Ic-68, Ic-71,        Ic-73, Ic-75, Ic-76, Ic-77, Ic-78, Ic-79, Ic-80, Ic-81, Ic-82,        Ic-83, Ic-84, Ic-85, Ic-93, Ic-110, Id-2, and Id-4.

BEST MODE FOR CARRYING OUT THE INVENTION

Compounds (I) of the invention may be synthesized for example accordingto any one of Method A to D.

Method A: A-4+A-5→I

in which V is a halogen, and other symbols are as defined above.

The method is a reaction known as Wittig reaction. First, halide (A-3)as a starting material is reacted with Wittig reagent (A-2) that isprepared from methyl triphenyl phosphonium halide (A-1) and butyllithium or the like, in an appropriate solvent to give A-4. Then, thecompound (A-4) is reacted with aromatic aldehyde (A-5) to give intendedvinyl derivative, diene derivative or triene derivative (I′). Thereaction may proceed at a temperature from room temperature to a refluxtemperature of the solvent.

Method B: B-2+B-3→I

in which R is a lower alkyl, and the symbols are as defined above.

B-1 (for example benzyl halide) and a alkyl phosphite are reacted in thepresence of a strong base such as a metallic sodium in an appropriatesolvent such as benzene or toluene at a temperature from roomtemperature to a reflux temperature of the solvent to give B-2 (forexample diethyl benzylphosphonate).

B-2 can be converted to compound (I) by reacting with one of variousaldehydes (B-3) in the presence of a quaternary alkyl ammonium salt andan alkali hydroxide such as lithium hydroxide at a temperature from roomtemperature to a reflux temperature of the solvent. The reaction mayproceed in a solvent such as methylene chloride, ethylene dichloride, ortetrahydrofuran.

Method C: C-1+C-2→I

in which the symbols are as defined above.

The method is a reaction known as Perkin reaction. Specifically, astarting material (C-1) and aldehydes (C-2) are reacted in anappropriate solvent such as acetic anhydride at a temperature from roomtemperature to a reflux temperature of the solvent to give compound(I″), which is a compound wherein m in formula (I) is 0, n is 1, and Y¹and Z¹ are H.

Method D: D-1+D-2→Ia

in which the symbols are as defined above.

Acetic acid derivative (D-1) and aldehydes (D-2) are reacted in thepresence of a base such as piperidine at a temperature from roomtemperature to a reflux temperature of the solvent to give compound(I′″), which is a compound wherein m in formula (I) is 0, n is 1, and Y¹is H. Benzene, toluene or pyridine may be used as a solvent.

The method of enhancing the expression of apoAI according to theinvention activates a reverse cholesterol transport activity of HDL, ananti-inflammatory activity and an anti-coagulant activity, or the like.As a result, the method of the invention are useful for preventingand/or treating dyslipidemia, arteriosclerotic diseases and variouscardiovascular diseases associated with them, which are caused bydecreased level of HDL in serum. “Dyslipidemia” specifically includeconditions of lowered level of serum HDL, hypercholesteremia andhypertriglyceridemia; “arteriosclerotic diseases” specifically includearteriosclerosis, myocardial infarction, and cardiac incompetence; and“various cardiovascular diseases associated with the above diseases”include hyperuricemia, coronary artery diseases, ischaemic heartdiseases, corneal opacity, cerebrovascular disease, and hereditary HDLdeficiencies (Tangier disease, fish-eye disease).

When a compound of the invention is administered in the method accordingto the invention, pharmaceutical compositions therefor may beadministered either orally or parenterally. For oral routes, thecompositions may be formulated conventionally into usual dosage formssuch as tablets, granules, powders, capsules, pills, solutions, syrups,buccals, sublinguals, or the like before administration. For parenteraladministration, the compositions may be conventionally formulated intousual dosage forms such as injections, e.g., intramuscular orintravenous injections, suppositories; transdermal patches, inhalation,or the like.

An effective amount of a compound according to the invention may beadmixed with various suitable pharmaceutical additives such asexcipient, binding agent, wetting agent, disintegrating agent,lubricant, diluent, or the like to give pharmaceutical compositions, ifnecessary. In the case of injections, the ingredients are sterilizedtogether with a suitable carrier to formulate the composition.

More specifically, the excipients include lactose, sucrose, glucose,starch, calcium carbonate, crystalline cellulose, or the like; thebinding agents include methyl cellulose, carboxymethylcellulose,hydroxypropylcellulose, gelatine, polyvinyl pyrrolidone, or the like;the disintegrating agents include carboxymethylcellulose, sodiumcarboxymethyl cellulose, starch, sodium alginate, algae powder, sodiumlauryl sulfate, or the like; the lubricants include talc, magnesiumstearate or Macrogol, or the like. Base materials of the suppository maybe for example cacao butter, Macrogol, methylcellulose, or the like.Solutions, emulsions or suspensions for injection may comprise asolubilizing agent, a suspending agent, an emulsifying agent, astabilizing agent, a preserving agent, an isotonic agent, or the like asusually used. Compositions for oral administration may comprise aflavoring agent, an aromatic agent, or the like.

Dose or therapeutically effective amount of the compounds according tothe invention for enhancing the expression of apoAI is preferablydetermined considering age and body weight of patients, sort andseverity of diseases to be treated, route of administration, or thelike. In the case of oral administration to an adult, the dose range isusually 1 to 100 mg/kg/day, preferably 5 to 30 mg/kg/day. In the case ofparenteral administration, the dose differs largely depending on theroute of administration, but the dose range is usually 0.1 to 10mg/kg/day, preferably 1 to 5 mg/kg/day. The dosage unit may beadministered to a subject once or several times per day.

Following examples and experiment are presented for purpose of furtherillustration of the invention, and they are not intended to limit thescope of the invention in any respect.

EXAMPLES Reference 1 3-(4-Ethoxycarbonylpropoxy)benzaldehyde (compoundC1)

A suspension of 3-hydroxybenzaldehyde (1.0 g, 8.19 mmol), ethyl4-bromobutyrate (1.76 g, 9.01 mmol), potassium carbonate (1.36 g, 9.83mmol), and dimethylformamide (20 ml) was stirred at room temperature for32 hours. To the reaction mixture were added ethyl 4-bromobutyrate (1.36g, 4.09 mmol) and potassium carbonate (0.594 g, 4.30 mmol), and then themixture was further stirred at 50° C. for 5 hours. After water was addedto the reaction, the mixture was extracted with ether, and the extractwas washed with water. The solvent was removed in vacuo. The residue wassubjected to silica gel chromatography using toluene-ethyl acetate (9:1)as eluent to give compound C1 (2.10 g) as pale yellow oil as a mixturecontaining a small amount of ethyl 4-bromobutyrate, which was used inthe subsequent reaction.

NMR(CDCl₃): 1.26 (3H, t, J=7.2), 2.10-2.22 (2H, m), 2.53 (2H, t, J=7.2),4.10 (2H, t, J=6.3), 4.16 (2H, q, J=7.2), 7.15-7.19 (1H, m), 7.37-7.38(1H, m), 7.43-7.47 (2H, m), 9.98 (1H, s).

Reference 2 Diethyl pyridin-2-yl-methyl phosphonate (compound B1)

2-Chloromethyl pyridine hydrochloride (75.7 g, 0.46 mol) was dissolvedin water (100 ml), and the solution was made alkaline by adding a 96%aqueous solution of sodium hydroxide (19.23 g, 0.46 mol) in water (200ml). The mixture was extracted with ether, and the extract was driedover anhydrous magnesium sulfate, after which the solvent was removed invacuo. The residue was purified by vacuum distillation to give2-chloromethylpyridine (52.72 g, 89.6%) as pale red oil.

Boiling point: 76-78° C./2133 Pa

To a solution of ethyl phosphite (57.07 g, 0.413 mol) in benzene (470ml) was added metallic sodium (9.50 g, 0.413 mol), and the mixture washeated at reflux for 4 hours, followed by adding dropwise the solutionof 2-chloromethyl pyridine (52.72 g, 0.413 mol) in benzene (350 ml) asdescribed above over 15 minutes at the same temperature. After heated atreflux for 2 hours, the reaction was allowed to cool to roomtemperature, and the benzene solution was washed with water, dried overanhydrous magnesium sulfate, and evaporated in vacuo. The residue wassubjected to silica gel chromatography using ethyl acetate-methanol(19:1) as eluent to give B1 (66.25 g, 69.9%) as oil.

Reference 3 1-Methoxymethylpyrrol-2-aldehyde (compound B2)

To a solution of pyrrol-2-carbaldehyde (951 m g, 10.00 mmol) indimethylsulfoxide (20 ml) were added a 4M aqueous sodium hydroxide (2.5ml, 10 mmol) and methoxymethyl chloride (0.84 ml, 11.00 mmol)sequentially, and the mixture was stirred at room temperature for 16hours. The reaction mixture was extracted with ether, and the extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and evaporated in vacuo. The residue was subjected tosilica gel chromatography using chloroform-acetonitrile (95:5) as eluentto give B2 (557 mg, 40%) as oil.

Reference 4 Methyl 2-hydroxy-5-methoxybenzoate (compound A1)

To a solution of 2-hydroxy-5-methoxybenzoic acid (6.0 g, 35.68 mmol) indimethylformamide (80 ml) were added sodium hydrogen carbonate (3.15 g,37.46 mmol) and methyl iodide (2.33 ml, 37.46 mmol), and the mixture wasstirred at 80° C. for 3 hours. After an ice water was added to thereaction, the mixture was extracted with ether, and the extract waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was removed in vacuo to give A1 (5.38 g,82.8%) as brown oil.

Reference 51-(2-Hydroxy-5-methoxyphenyl)-2-(triphenyl-phosphoridene)ethanone(compound A2)

To sodium hydride (60%, 305 mg, 7.62 mmol) rinsed with hexane was addeda solution of methyl benzoate A1 described in Reference 4 (500 mg, 2.74mmol) in dimethylformamide (20 ml), and the mixture was stirred at 80°C. for 45 minutes. After cooled to below 20° C.,methyltriphenylphosphonium bromide (1.96 g, 5.49 mmol) was addeddropwise, and the mixture was stirred at room temperature for 30 minutesand then at 80° C. for 22 hours. After an ice water was added to thereaction, the mixture was extracted with ether, and the extract waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was removed in vacuo. The residue wassubjected to silica gel chromatography using ethyl acetate-hexane (1:1)as eluent to give compound A2 (407 mg, 34.8%) as pale yellow oil.

NMR(CDCl₃): 3.77 (3H, s), 6.81 (1H, d, J=9.0), 6.89 (1H, dd, J=3.0,9.0), 7.23 (1H, d, J=3.0), 7.47-7.74 (16H, m)

Reference 6 4-Methylcinnamaldehyde (compound B3)

To a solution of sodium hydroxide (2.0 g, 50 mmol) in a mixture ofethanol (12 ml) and water (24 ml) was added p-tolualdehyde (9.0 g, 74.9mmol), and the mixture was stirred at 0° C. for 15 minutes, and then 40%acetaldehyde (20 g, 181.6 mmol) was added dropwise over 4 hours. Aftercooled to 0° C., the reaction mixture was neutralized with 20% aceticacid. Then, the mixture was extracted with ether, and the extract waswashed with saturated brine, dried over anhydrous magnesium sulfate, andevaporated in vacuo. The residue was subjected to silica gelchromatography using isopropylether-hexane (1:2) as eluent to give B3(6.03 g, 55.1%) as oil.

Reference 7 3-(3-Thienyl)acrolein (compound B4)

To a solution of sodium hydroxide (1.0 g, 25 mmol) in a mixture ofethanol (6 ml) and water (12 ml) was added thiophen-3-carbaldehyde (4.5g, 40.1 mmol), and the mixture was stirred at 0° C. for 10 minute. Tothe mixture was dropwise added 40% acetaldehyde (10 g, 90.8 mmol) over 3hours at the same temperature, and the mixture was further stirred for30 minutes. The reaction mixture was treated in a similar manner to thatin Reference 6 to give compound B4 (3.58 g, 64.6%) as oil.

Example 1 2-[2-(4-chlorophenyl)vinyl]quinoxaline (Ib-65)

Method A: To a solution of methyl triphenyl phosphonium bromide (11.86g, 33.2 mmol) in tetrahydrofuran (100 ml) was added dropwise n-butyllithium (a 1.66 M solution in hexane, 20 ml, 33.2 mmol) at roomtemperature. The mixture was stirred for 30 minutes at the sametemperature, and then heated at reflux for an hour. After the reactionmixture was cooled to room temperature, 2-chloroquinoxaline (2.73 g,16.6 mmol; U.S. Pat. No. 2,573,870: C.A., 45, 4274 (1951)) was added,and the mixture was stirred at room temperature for 2 hours. Then,4-chlorobenzaldehyde (2.33 g, 16.6 mmol) was added, and the mixture wasstirred for 30 minutes. After the insoluble materials were removed byfiltration, and washed with tetrahydrofuran, the filtrate and thewashing were combined, and concentrated in vacuo. The residue wassubjected to silica gel chromatography using chloroform-acetone (19:1)as eluent, and then recrystallized from ethyl acetate to give Ib-65(2.70 g, 61%) as yellow crystal.

Example 2 4-(2-Quinoxaline-2-yl-vinyl)benzoic acid (Ib-59)

To a solution of Ib-58 (410 mg, 1.40 mmol) as obtained in a similarmanner to Example 1 in methanol (4 ml) and tetrahydrofuran (4 ml) wasadded 1M aqueous sodium hydroxide (3 ml, 3.00 mmol), and the mixture wasstirred at room temperature for 2 hours. Water was added, and themixture was washed with ethyl acetate. The aqueous alkaline layer wasmade acidic with hydrochloric acid, and the precipitated crystals werecollected by filtration. Recrystallization from methanol gave Ib-59 (336mg, 86%).

Example 3 4-(2-Quinoxaline-2-ylvinyl)phenylamine (Ib-69)

To a solution of N-[4-(2-quinoxaline-2-ylvinyl)phenyl]acetamide (Ib-70,289 m g, 1.00 mmol) as obtained in a similar manner to Example 1 inethanol (1.6 ml) and water (1.6 ml) was added 1M potassium hydroxide(0.80 g, 14.26 mmol), and the mixture was heated to reflux for 4 hours.The reaction was neutralized by adding acetic acid under ice cooling,and the precipitated crystals were collected by filtration, andrecrystallization from methanol gave Ib-69 (107 mg, 43%).

Example 4 Ethyl 4-[3-(2-quinoline-2-yl-vinyl)phenoxy]butanoate (Ib-88)

Method C: To quinaldine (1.00 g, 6.95 mmol) were added compound C1 (1.80g, 7.65 mmol) as described in Reference 1 and acetic anhydride (1.31 ml,13.9 mmol), and the mixture was stirred at 150° C. for 5 hours. Thesolvent was removed in vacuo, and the residue was subjected to silicagel chromatography using toluene-ethyl acetate (9:1) as eluent.Recrystallization from ethyl acetate-hexane gave Ib-88 (1.09 g, 43.4%)as colorless crystal.

Example 5 4-[3-(2-quinoline-2-yl-vinyl)phenoxy]butanoic acid (Ib-89)

To a solution of Ib-88 (100 mg, 0.277 mmol) prepared in Example 4 1 inmethanol (1 ml) and tetrahydrofuran (1 ml) was added 1N aqueouspotassium hydroxide (0.66 ml, 0.66 mmol), and the mixture was stirred atroom temperature for 25 hours, after which the reaction was concentratedin vacuo. After ice water was added to the residue, the mixture was madeweak acid by adding 1N aqueous hydrochloric acid, and extracted withethyl acetate. The extract was washed with water and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was removed invacuo to give the residue, which was recrystallized fromacetone-isopropylether to give Ib-89 (69 mg, 75%).

Example 6 2-Styryl-pyridine (Ib-1)

Method B: To a solution of compound B1 (458 mg, 2.00 mmol) indichloromethane (2 ml) were added benzaldehyde (212 mg, 2.00 mmol), 48%aqueous sodium hydroxide (1.2 ml) and tetrabutylammonium iodide (60 mg,0.16 mmol), and the mixture was stirred at room temperature for 1 hour.After water was added to the reaction, the mixture was extracted withether, and the extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate, and evaporated in vacuo. The residuewas recrystallized from isopropylether to give Ib-1 (242 mg, 67%).

Example 7 2-(2-Thiophen-3-yl-vinyl)pyridine (Ib-52)

Method B: To a solution of compound B1 (5.339 g, 23.29 mmol) describedin Reference 2 in dichloromethane (23 ml) were addedthiophen-3-carbaldehyde (2.612 g, 23.29 mmol), 48% aqueous sodiumhydroxide (14.0 ml) and tetrabutylammonium iodide (0.700 g, 1.90 mmol),and the mixture was stirred at room temperature for 3 hours. Thereaction was treated in a similar manner to Example 7. The residue wassubjected to silica gel chromatography using chloroform-acetonitrile(19:1), and recrystallization from acetone-isopropylether gave Ib-52(2.67 g, 61.2%).

Method D:

To a solution of 2-pyridylacetic acid hydrochloride (868 mg, 5.00 mmol)and thiophen-3-cabaldehyde (841 mg, 7.50 mmol) in pyridine (7.5 ml) wasadded piperidine (0.05 ml, 0.51 mmol), and the mixture was heated atreflux for 20 hours. After the solvent was removed from the reaction invacuo, the residue was extracted with ethyl acetate, and the extract waswashed sequentially with 1M aqueous sodium hydroxide, water andsaturated brine, and dried over anhydrous magnesium sulfate. The residuewas subjected to silica gel chromatography using chloroform-acetonitrile(19:1). Recrystallization from acetone-isopropylether gave Ib-52 (198mg, 21.2%).

Example 8 2-(4-phenylbuta-1,3-dienyl)quinoxaline (Ic-68)

Method A: To a solution of methyltriphenylphosphonium bromide (2.20 g,6.16 mmol) in tetrahydrofuran (10 ml) was added n-butyl lithium (1.66 Msolution in hexane, 4 ml, 6.16 mmol) at room temperature in a nitrogenatmosphere. After stirred for 40 minutes, 2-chloroquinoxaline (0.507 g,3.08 mmol) was added, and the mixture was stirred at room temperaturefor 2 hours. Then, cinnamaldehyde (0.407 g, 3.08 mmol) was added, andthe mixture was stirred for an hour. The reaction mixture was subjectedto silica gel chromatography using ethyl acetate-hexane (1:2) as eluent.Recrystallization from ethyl acetate-hexane gave Ic-68 (0.148 g, 18.6%).

Example 9 2-(4-Phenylbuta-1,3-dienyl)pyridine (Ic-1)

Method B: A solution of compound B1 (10.25 g, 44.7 mmol) described inReference 2 and cinnamaldehyde (5.91 g, 44.7 mmol) in methylene chloride(6 ml) was dropwise added to a solution of 48% aqueous sodium hydroxide(26 ml) and tetrabutylammonium iodide (0.9 g, 2.4 mmol) in methylenechloride (47 ml) over 10 minutes at room temperature, and the mixturewas stirred for 15 minutes. Then, the mixture was heated at reflux foran hour. After ice water was added, the mixture was extracted withtoluene, and the extract was washed with water, dried over anhydrousmagnesium sulfate, and evaporated in vacuo. The residue was subjected tosilica gel chromatography using chloroform-hexane (4:1) as eluent.Recrystallization from ethyl acetate-hexane gave Ic-1 (3.95 g, 42.6%).

Example 10 2-(4-p-tolyl-buta-1,3-dienyl)-pyridine (Ic-6)

Method B: Compound B1 (8.251 g, 36.0 mmol) described in Reference 2,Compound B3 (5.262 g, 36.0 mmol) described in Reference 6,tetrabutylammonium iodide (1.08 g, 2.9 mmol) and 48% aqueous sodiumhydroxide (21.6 ml) were stirred in dichloromethane (44 ml) at roomtemperature for an hour. The reaction was treated in a similar manner toExample 9, and the residue was subjected to silica gel chromatographyusing ethyl acetate-hexane (1:2) as eluent. Recrystallizing from ethylacetate-hexane gave Ic-6 (2.28 g, 28.6%).

Example 11 2-(4-Thiophen-3-yl-buta-1,3-dienyl)pyridine (Ic-82)

Method B: Compound B1 (3.577 g, 15.6 mmol) described in Reference 2, thealdehyde (B4, 2.156 g, 15.6 mmol) described in Reference 7,tetrabutylammonium iodide (0.47 g, 1.27 mmol) and 48% aqueous sodiumhydroxide (9.5 ml) were heated at reflux in dichloromethane (19.6 ml)for an hour. The reaction was treated in a similar manner to Example 9,and the residue was subjected to silica gel chromatography usingtoluene-hexane (9:1) as eluent. Recrystallizing from ethylacetate-hexane gave Ic-82 (1.453 g, 43.7%).

In a similar manner, other compounds were prepared, of which chemicalstructures are shown in the following tables.

TABLE 1 Ia

Ar² Ia-1

Ia-2

Ia-3

Ia-4

Ia-5

Ia-6

Ia-7

Ia-8

Ia-9

Ia-10

Ia-11

Ia-12

Ia-13

Ia-14

Ia-15

Ia-16

Ia-17

Ia-18

Ia-19

Ia-20

Ia-21

Ia-22

TABLE 2 Ib

Ar¹ (salt) Ar² Ib-1

Ib-2

Ib-3

Ib-4

Ib-5

Ib-6

Ib-7

Ib-8

(MeI)

Ib-9

Ib-10

(MeI)

Ib-11

Ib-12

Ib-13

Ib-14

Ib-15

(2HCl)

Ib-16

Ib-17

Ib-18

(MeI)

Ib-19

Ib-20

Ib-21

Ib-22

Ib-23

Ib-24

Ib-25

Ib-26

Ib-27

Ib-28

Ib-29

Ib-30

Ib-31

Ib-32

Ib-33

Ib-34

Ib-35

Ib-36

TABLE 3 Ib

Ar¹ (salt) Ar² Ib-37

Ib-38

Ib-39

Ib-40

Ib-41

Ib-42

(MeI)

Ib-43

Ib-44

(MeI)

Ib-45

Ib-46

Ib-47

Ib-48

Ib-49

Ib-50

Ib-51

Ib-52

Ib-53

Ib-54

Ib-55

Ib-56

Ib-57

Ib-58

Ib-59

Ib-60

Ib-61

Ib-62

Ib-63

Ib-64

Ib-65

Ib-66

Ib-67

Ib-68

Ib-69

Ib-70

Ib-71

Ib-72

TABLE 4 Ib

Ar¹ Z¹ Ar² Ib-73

H

Ib-74

H

Ib-75

H

Ib-76

H

Ib-77

H

Ib-78

H

Ib-79

H

Ib-80

H

Ib-81

H

Ib-82

H

Ib-83

H

Ib-84

H

Ib-85

H

Ib-86

H

Ib-87

H

Ib-88

H

Ib-89

H

Ib-90

H

Ib-91

H

Ib-92

H

Ib-93

H

Ib-94

H

Ib-95

H

Ib-96

H

Ib-97

H

Ib-98

H

Ib-99

H

Ib-100

H

Ib-101

CN

Ib-102

H

Ib-103

H

TABLE 5 Ic

Ar¹ Ar² Ic-1

Ic-2

Ic-3

Ic-4

Ic-5

Ic-6

Ic-7

Ic-8

Ic-9

Ic-10

Ic-11

Ic-12

Ic-13

Ic-14

Ic-15

Ic-16

Ic-17

Ic-18

Ic-19

Ic-20

Ic-21

Ic-22

Ic-23

Ic-24

Ic-25

Ic-26

Ic-27

Ic-28

Ic-29

Ic-30

Ic-31

Ic-32

Ic-33

Ic-34

Ic-35

Ic-36

TABLE 6 Ic

Ar¹ Z¹ Ar² Ic-37

H

Ic-38

H

Ic-39

H

Ic-40

H

Ic-41

H

Ic-42

H

Ic-43

H

Ic-44

H

Ic-45

H

Ic-46

H

Ic-47

H

(MeI) Ic-48

H

Ic-49

H

Ic-50

H

Ic-51

H

Ic-52

H

Ic-53

H

Ic-54

H

Ic-55

H

Ic-56

H

Ic-57

H

Ic-58

H

Ic-59

H

Ic-60

H

Ic-61

H

Ic-62

H

Ic-63

H

Ic-64

H

Ic-65

H

Ic-66

H

Ic-67

H

Ic-68

H

Ic-69

H

Ic-70

H

Ic-71

Me

Ic-72

Pen

Ic-73

Br

TABLE 7 Ic

Ar¹ n Y¹ Z¹ Ar² Ic-74

1

H

Ic-75

1 Me H

Ic-76

1 Me H

((COOH)₂) Ic-77

1 CN H

Ic-78

1 H H

Ic-79

1 H H

Ic-80

1 H H

(HCl) Ic-81

1 H H

Ic-82

1 H H

Ic-83

1 H H

Ic-84

1 H H

Ic-85

1 H H

Ic-86

1 H H

Ic-87

1 H H

Ic-88

1 H H

Ic-89

1 H H

Ic-90

1 H H

Ic-91

1 H H

Ic-92

1 H H

Ic-93

2 H H

Ic-94

2 H H

Ic-95

2 H H

Ic-96

2 H H

Ic-97

2 H H

Ic-98

2 H H

Ic-99

2 H Me

Ic-100

2 Me H

Ic-101

2 CN H

Ic-102

2 H H

Ic-103

2 H H

Ic-104

2 H H

Ic-105

2 H H

Ic-106

2 H H

Ic-107

2 H H

Ic-108

2 H H

Ic-109

2 H H

(MeI) Ic-110

1 H CH₂O—*

Ic-111

1 Cl CH₂S—*

“CH₂O—*” and “CH₂S—*” each combine with * or Ar²

TABLE 8 Id

Ar¹ X Y¹ Z¹ Ar² Id-1

CH₂ H H

Id-2

CH₂CH₂ H H

Id-3

CH₂CH₂ H H

Id-4

S H H

(HCl) Id-5

NH H H

Id-6

N═CH H H

TABLE 9 Elemental Elemental Com- m.p Molecular anylysis anylysis pound(° C.) *4 formula (Calculated) (Found) NMR Ia-1 76.5-78   C14H10N2 C,81.53; H, 4.89; C, 81.48; H, 4.98; 7.49-7.63(3H, m), 7.72-7.84(2H, m),8.10-8.24(4H, m), 9.34 N, 13.58 N, 13.27 (1H, s) Ia-2 138-139 C14H9C11N2C, 69.86; H, 3.77; C, 70.11; H, 3.65; 7.54(2H, d, J=8.4), 7.72-7.85(2H,m), 8.10-8.17(2H, m), Cl, 14.73; N, 65;Cl, 14.58; 8.16(2H, d, J=9.0),9.30(1H, s) 11.64 N, 11.78 Ia-3 101-102 C15H12N2O1 C, 76.25; H, 5.12; C,76.16; H, 5.08; 3.90(3H, s), 7.08(2H, d, J=8.8), 7.66-7.82(2H, m),8.02-8.14 N, 11.85 N, 12.06 8.14(2H, m), 8.18(2H, d, J=9.2), 9.29(1H, s)Ia-6 86-87 C12H8N2S1 C, 67.90; H, 3.80; C, 67.82; H, 3.54; 7.50(1H, dd,J=3.0, 5.2), 7.67-7.81(2H, m), 7.92(1H, dd, N, 13.19; S, N, 13.29; S,J=1.6, 5.2), 8.06-8.12(2H, m), 8.16(1H, dd, J=1.2, 3.0), 15.10 15.119.23(1H, s) Ia-10 126-127 C20H14N2 C, 85.08; H, 5.00; C, 85.33; H, 4.75;7.38-7.52(1H, m), 7.46-7.52(2H, m), 7.67-7.70(2H, m), N, 9.92 N, 9.877.73-7.78(2H, m), 7.81(2H, d, J=8.4), 8.12-8.19(2H, m), 8.30 (2H, d,J=8.4), 9.38(1H, s) Ia-12 180-182 C21H15N1 C, 89.65; H, 5.37; C, 89.87;H, 5.38; 7.35-7.40(1H, m), 7.47(2H, t, J=7.8), 7.53(1H, dt, J=1.2, N,4.98 N, 5.06 7.5), 7.66-7.76(3H, m), 7.76(2H, d, J=8.1), 7.83(1H, d,J=8.4), 7.93(1H, d, J=8.4), 8.18(1H, d, J=8.4), 8.23(1H, d, J=7.2),8.26(2H, d, J=8.4) Ia-13 on sale Ia-14 120-123 C16H13NO C, 81.68; H,5.57; C, 81.74; H, 5.50; 3.89(3H, s), 7.05(2H, d, J=9.0), 7.45-7.86(4H,m), 8.10-8.20 N, 5.95 N, 5.99 (2H, m), 8.14(2H, d, J=9.0) Ia-15 132-133C13H9NS C, 73.90; H, 4.29; C, 73.96; H, 4.24; 7.44(1H, dd, J=3.0 and5.1), 7.47-7.53(1H, m), 7.66-7.82 N, 6.33; S, N, 6.61; S, (3H, m),7.88(1H, dd, J=1.2 and 5.1), 8.05(1H, dd, J=1.2 15.18 14.89 and 3.0),8.08-8.20(2H, m) Ia-16 113-115 C15H10ClN C, 75.16; H, 4.20; C, 75.09; H,4.11; 7.44-7.57(1H, m), 7.50(2H, d, J=8.7), 7.69-7.88(3H, m), N, 5.84;Cl, N, 5.73; Cl, 8.08-8.26(2H, m), 8.13(2H, d, J=8.7) 14.79 14.49*1)Solvent 1)CDC13 + CD3OD 2)DMSO-6d 3)D2O 4)Oils in case of no value

TABLE 10 Ia-17 153-156 C22H17N1 C, 89.46; H, 5.80; C, 89.43; H, 5.80;2.79(3H, s), 7.36-7.40(1H, m), 7.47(2H, t, J=7.5), 7.55 N, 4.74 N, 4.79(1H, dt, J=1.5, 7.6), 7.68(2H, dd, J=2.1, 7.5), 7.72-7.77 (2H, m),7.75(2H, d, J=8.1), 8.01(1H, dd, J=1.5, 8.4), 8.19(1H, dd, J=0.6, 9.0),8.24(2H, d, J=8.4) Ia-18 49-50 C15H11N C, 87.77; H, 5.40; C, 87.75; H,5.50; 7.39-7.95(8H, m), 8.16(1H, d, J=8.4), 8.32(1H, d, J=2.2), N, 6.82N, 6.96 9.19(1H, d, J=2.6) Ia-19 233-234 C14H12N2O C, 74.21; H, 5.54; C,74.20; H, 5.66; CDC13) 3.85(3H, s), 3.95(1H, br), 6.98(2H, d, J=8.8),7.25 0.1AcOEt N, 12.02 N, 11.73 25(2H, dd, J=3.2 and 6.0), 7.62(2H, dd,J=3.2 and 6.0), 8.01(2H, d, J=8.8) Ia-20 on sale Ia-21 on sale Ia-2295-97 C14H11NO2 C, 74.65; H, 4.92; C, 74.43; H, 4.98; CDC13) 3.90(3H,s), 7.03(2H, d, J=8.8), 7.23-7.40(2H, m), N, 6.22 N, 6.31 7.43-7.62(1H,m), 7.68-7.79(1H, m), 8.20(2H, d, J=8.8) Ib-1 89-91 C13H11N C, 86.15; H,6.12; C, 86.14; H, 6.09; 7.13-7.17(1H, m), 7.17(1H, d, J=16.2),7.30-7.41(4H, m), N, 7.73 N, 7.80 7.57-7.69(4H, m), 8.60-8.62(1H, m)Ib-8 on sale Ib-9 122-124 C14H10NF3 C, 67.45; H, 4.04; C, 67.31; H,4.06; 7.17-7.20(1H, m), 7.24(1H, d, J=15.3), 7.40(1H, d, J=8.1), N,5.62; F, N, 5.67; S, 7.61-7.73(6H, m), 8.62-8.64(1H, m) 22.87 22.71Ib-10 on sale Ib-11 on sale Ib-15 on sale Ib-17 128 C17H13N1 C, 88.28;H, 5.67; C, 88.17; H, 5.73; 7.13-7.19(1H, m), 7.33-7.50(3H, m), 7.45(1H,d, J=16.4), N, 6.06 N, 6.04 7.68(1H, dt, J=1.8, 7.7), 7.76-7.87(5H, m),7.90(1H, d, J=16.2), 8.63(1H, d, J=4.6) Ib-18 on sale Ib-33 82-83C15H11N1O1 C, 81.43; H, 5.01; C, 81.18; H, 5.03; 6.79(1H, s),7.13-7.33(4H, m), 7.32(1H, d, J=15.8), 7.46-7.58 N, 6.33 N, 6.53 (2H,m), 7.62(1H, d, J=15.8), 7.67(1H, dt, J=1.8, 7.6), 8.61(1H, d, J=4.4)

TABLE 11 Ib-34 122-124 C14H10N2S1 C, 70.56; H, 4.23; C, 70.67; H, 4.30;7.12-7.28(1H, m), 7.35-7.53(3H, m), 7.62(1H, d, J=16.2), 7.72 N, 11.75;S, N, 11.75; S, (1H, dt, J=1.8, 7.7), 7.84-7.90(1H, m), 7.88(1H, d,J=15.8), 13.45 13.44 8.04(1H, d, J=7.6), 8.66(1H, d, J=4.4) Ib-35 73-74C15H11N1O1 C, 81.43; H, 5.01; C, 81.51; H, 5.10; 7.12-7.19(1H, m),7.28(1H, d, J=16.2), 7.34-7.40(2H, m), N, 6.33 N, 6.47 7.50-7.55(1H, m),7.67(1H, dt, J=1.6, 7.7), 7.45(1H, d, J=16.2), 7.85(1H, s), 7.99(1H, m),8.61(1H, d, J=4.4) Ib-36 73-75 C16H14N2 C, 82.02; H, 6.02; C, 82.00; H,5.87; 3.80(3H, s), 7.03-7.10(1H, m), 7.15(1H, d, J=16.2), 7.19-7.36 N,11.96 N, 11.95 (4H, m), 7.62(1H, dt, J=1.8, 7.6), 7.84(1H, d, J=16.6),8.04(1H, dd, J=1.8, 6.6), 8.57(1H, d, J=4.8) Ib-41 121.5- C12H10N2 C,79.10; H, 5.53; C, 79.23; H, 5.49; 7.16-7.26(2H, m), 7.41-7.45(2H, m),7.66-7.71(4H, m), 122 N, 15.37 N, 15.32 8.62-8.65(2H, m) Ib-42 on saleIb-43 oil C12H10N2 C, 78.79; H, 5.51; C, 78.42; H, 5.59; 7.17-7.33(3H,m), 7.50(1H, d, J=8.1), 7.61-7.72(2H, m), N, 15.31 N, 15.277.87-7.91(1H, m), 8.52-8.53(1H, m), 8.62-8.63(1H, m), Ib-44 on sale8.80(1H, s) Ib-45 70-73 C12H10N2 0.1H2O C, 78.32; H, 5.58; C, 78.22; H,5.67; 7.20-7.24(1H, m), 7.34(1H, d, J=16.2), 7.41-7.44(3H, m), 7.58 N,15.22 N, 15.10 (1H, d, J=16.2), 7.68-7.74(1H, m), 8.61-8.66(3H, m) Ib-46103.5- C11H9NS C, 70.55; H, 4.84; C, 70.55; H, 4.84; 6.89(1H, d,J=16.2), 7.18(1H, d, J=16.2), 7.27-7.37(4H, m), 105 N, 7.48; S, N, 7.45,S, 7.78-7.82(1H, m), 8.481H, br), 8.70(1H, br) 17.12 17.16 Ib-47 180-182C11H9NS C, 70.55; H, 4.84; C, 70.37; H, 4.83; 6.85(1H, d, J=16.2),7.26-7.38(6H, m), 8.57(2H, br) N, 7.48; S, N, 7.59, S, 17.12 17.19 Ib-48113.5- C1H8N2S C, 63.80; H, 4.28; C, 63.95; H, 4.26; 6.89(1H, d,J=15.9), 7.25-7.29(1H, m), 7.35-7.41(2H, m), 114.5 N, 14.88; S, N,14.55; S, 7.49-7.51(1H, m), 7.90(1H, d, J=15.9), 8.66(1H, br), 9.15(1H,s) 17.03, 16.90 Ib-49 74-76 C10H8N2S.0.1H2O C, 63.20; H, 4.24; C, 63.31;H, 4.27; 6.99(1H, d, J=15.9), 7.26-7.44(3H, m), 7.75(1H, d, J=15.9), N,14.74; S, N, 14.57; S, 8.39(1H, br), 8.53(1H, br), 8.61(1H, br) 16.8716.99

TABLE 12 Ib-50 95-96 C1H12N2 C, 78.23; H, 6.56, C, 78.37; H, 6.59;3.75(3H, s), 6.16-6.18(1H, m), 6.59-6.61(1H, m), N, 15.20 N, 15.286.67-6.68(1H, m), 6.90(1H, d, J=15.3), 7.05-7.10(1H, m), 7.23-7.26(1H,m), 7.56-7.63(2H, m), 8.55-8.57(1H, m) Ib-51 oil C13H14N2O C, 72.27; H,6.53; C, 72.22; H, 6.52; 3.28(3H, s), 5.33(2H, s), 6.21-6.23(1H, m),6.64-6.65(1H, m), 0.1H2O N, 12.96 N, 12.96 6.82-6.83(1H, m), 6.97(1H, d,J=16.2), 7.05-7.10(1H, m), 7.28-7.31(1H, m), 7.58-7.63(1H, m), 7.63(1H,d, J=16.2), 8.55-8.57(1H, m) Ib-52   97-98.5 C11H9NS C, 70.55; H, 4.84;C, 70.54; H, 4.75; 7.01(1H, d, J=16.0), 7.10-7.16(1H, m), 7.31-7.40(4H,m), N, 7.48; S, N 7.65; S, 7.60-7.68(2H, m), 8.58-8.59(1H, m) 17.1217.34 Ib-53 84-85 C11H9N101 C, 77.17; H, 5.30; C, 76.90; H, 5.40;6.68(1H, m), 6.88(1H, d, J=16.2), 7.08-7.15(1H, m), 7.31(1H, N, 8.18 N,8.07 d, J=8.2), 7.42(1H, m), 7.50(1H, d, J=16.2), 7.59(1H, s), 7.64 (1H,dt, J=1.8, 7.7), 8.56(1H, d, J=4.6) Ib-54 232-233 C11H11N3 C, 71.33; H,5.99; C, 71.18; H, 5.99; *2) 2.28(3H, s), 6.85-7.19(2H, m), 7.45(1H, d,J=7.6), 7.52 N, 22.68 N, 22.43 (2H, d, J=15.8), 7.70(1H, dt, J=1.6,8.1), 8.50(1H, d, J=3.6) Ib-55 61-63 C12H12N3Cl C, 61.67; H, 5.18; C,61.68; H, 5.32; 2.43(3H, s), 3.81(3H, s), 7.04(1H, d, J=16.5),7.10-7.14(1H, N, 17.98; Cl, N, 18.21; Cl, m), 7.34(1H, d, J=7.8),7.44(1H, d, J=16.5), 7.61-7.67(1H, m), 15.17 15.12 8.58-8.60(1H, m)Ib-56 107-108 C16H12N2 C, 82.73; H, 5.21; C, 82.57; H, 5.07; 7.39(1H, d,J=16.6), 7.36-7.48(3H, m), 7.65-7.81(4H, m), 7.88 N, 12.06 N, 11.99 (1H,d, J=16.6), 8.08(1H, dd, J=2.4, 6.8), 9.05(1H, s) Ib-57 117-119 C17H14N2C, 82.90; H, 5.73; C, 83.12; H, 5.73; 2.40(3H, s), 7.24(2H, d, J=8.4),7.34(1H, d, J=16.0), 7.56(2H, N, 11.37 N, 11.17 d, J=8.4), 7.65-7.81(2H,m), 7.85(1H, d, J=16.0), 8.06(2H, m), 9.04(1H, s) Ib-58 162-163C18H14N2O2 C, 74.47; H, 4.86; C, 74.41; H, 4.85; 3.94(3H, s), 7.47(1H,d, J=16.2), 7.72(2H, d, J=8.4), 7.72-7.81 N, 9.65 N, 9.55 (2H, m),7.91(1H, d, J=16.6), 8.08(2H, m), 8.09(2H, d, J=8.4), 9.05(1H, s)Ib-59 >300 C17H12N2O2 C, 73.90; H, 4.38; C, 73.81; H, 4.39; *2) 3.38(1H,br.s), 7.72(1H, d, J=16.6), 7.78-7.85(2H, m), 7.90 N, 10.14 N, 10.21(2H, d, J=8.0), 8.01(2H, d, J=8.8), 8.07(1H, d, J=15.8), 8.09 (2H, m),9.30(1H, s)

TABLE 13 Ib-60 206-208 C17H11N3 C, 79.36; H, 4.31; C, 79.47; H, 4.37;7.47(1H, d, J=16.0), 7.70(2H, d, J=8.8), 7.75(2H, d, J=8.8), N, 16.33 N,16.26 7.74-7.83(2H, m), 7.89(1H, d, J=16.6), 8.07-8.12(2H, m), 9.04(1H,s) Ib-61 131-133 C22H16N2 C, 85.68; H, 5.23; C, 85.97; H, 5.13;7.37-7.51(3H, m), 7.43(1H, d, J=16.4), 7.62-7.82(4H, m), N, 9.08 N, 9.237.66(2H, d, J=8.8), 7.75(2H, d, J=8.4), 7.92(1H, d, J=16.6), 8.08(2H,dd, J=2.6, 7.8), 9.06(1H, s) Ib-64 124-126 C16H11F1N2 C, 76.79; H, 4.43;C, 76.89; H, 4.43; 7.12(2H, t, J=8.6), 7.30(1H, d, J=16.0),7.60-7.77(4H, m), F, 7.59; N, F, 7.35; N, 7.84(1H, d, J=16.4),8.04-8.10(2H, m), 9.02(1H, s) 11.19 11.23 Ib-65 144-145 C16H11Cl1N2 C,72.05; H, 4.16; C, 72.05; H, 4.05; 7.35(1H, d, J=16.2), 7.39(2H, d,J=8.4), 7.59(2H, d, J=8.4), Cl, 13.29; N, Cl, 13.09; 7.67-7.82(2H, m),7.83(1H, d, J=16.6), 8.04-8.10(2H, 10.50 N, 10.47 m), 9.02(1H, s) Ib-66164-165 C16H11Br1N2 C, 61.76; H, 3.56; C, 61.58; H, 3.58; 7.36(1H, d,J=16.0), 7.51(2H, d, J=8.4), 7.56(2H, d, J=8.4), Br, 25.68; N, Br,25.52; 7.67-7.82(2H, m), 7.82(1H, d, J=16.2), 8.04-8.10(2H, 9.00 N, 8.98m), 9.02(1H, s) Ib-67 130-131 C17H14N2O1 C, 77.84; H, 5.38; C, 78.13; H,5.36; 6.95(2H, d, J=8.8), 7.25(1H, d, J=16.6), 7.61(2H, d, J=8.8), N,10.68 N, 10.70 7.65-7.78(2H, m), 7.83(1H, d, J=16.4), 8.05(2H, td,J=2.0, 7.4), 9.02(1H, s) Ib-68 234-235 C1612N2O1 C, 77.40; H, 4.87; C,77.36; H, 4.81; *1) 6.89(2H, d, J=8.8), 7.21(1H, d, J=16.4), 7.55(2H, d,N, 11.28 N, 11.39 J=8.8), 7.65-7.81(2H, m), 7.80(1H, d, J=16.0),8.04(2H, dd, J=2.2, 7.6), 9.03(1H, s) Ib-69 166-167 C16H13N3 C, 77.15;H, 5.34; C, 77.12; H, 5.03; 1.2-4.4(2H, br.), 6.71(2H, d, J=8.4),7.19(1H, d, J=16.4), 0.1H2O N, 16.87 N, 16.98 7.49(2H, d, J=8.6),7.62-7.77(2H, m), 7.79(1H, d, J=16.0), 8.01-8.06(2H, m), 9.00(1H, s)Ib-70 225-227 C18H15N3O1 C, 73.37; H, 5.33; C, 13.37; H, 5.31; *1)2.19(3H, s), 7.31(1H, d, J=16.6), 7.61(4H, s), 7.67-7.82 0.3H2O N, 14.26N, 14.21 (2H, m), 7.82(1H, d, J=16.4), 8.06(2H, dd, J=2.2, 7.4),9.03(1H, s) Ib-72 121-122 C22H16N2O1 C, 81.46: H, 4.97; C, 81.83; H,4.91; 7.04(2H, d, J=8.8), 7.09-7.42(5H, m), 7.29(1H, d, J=16.2), N, 8.63N, 8.50 7.63(2H, d, J=8.8), 7.69-7.79(2H, m), 7.85(1H, d, J=16.0),8.08(2H, td, J=2.2, 7.2), 9.03(1H, s)

TABLE 14 Ib-73 98-101 C14H10N2O1 C, 75.66; H, 4.54; C, 75.56; H, 4.56;6.50(1H, dd, J=1.5, 3.3), 6.61(1H, d, J=3.0), 7.29(1H, d, J=15.9), N,12.60 N, 12.75 7.51(1H, d, J=1.5), 7.66-7.78(2H, m), 7.72(1H, d,J=16.2), 8.03-8.07(2H, m), 8.93(1H, s) Ib-74 97-99 C14H10N2S1 C, 70.56;H, 4.23; C, 70.39; H, 4.13; 7.08(1H, dd, J=3.6, 5.2), 7.17(1H, d,J=16.2), 7.30(1H, d, N, 11.75; S, N, 11.96; S, J=3.4), 7.35(1H, d,J=5.0), 7.65-7.80(2H, m), 7.98-8.08(2H, 13.45 13.44 m), 8.03(1H, d,J=16.2), 8.96(1H, s) Ib-75 107-109 C14H10N2O1 C, 75.66; H, 4.54; C,75.78; H, 4.51; 6.77(1H, m), 7.12(1H, d, J=16.2), 7.48(1H, m),7.67-7.79(3H, N, 12.60 N, 12.56 m), 7.77(1H, d, J=16.2), 8.03-8.08(2H,m), 8.99(1H, s) Ib-77 97-99 C14H10N2S1 C, 70.56; H, 4.23; C, 70.39; H,4.25; 7.21(1H, d, J=16.0), 7.39(1H, dd, J=3.0, 5.2), 7.47(1H, dd, N,11.75; S, N, 11.86; S, J=1.0, 5.2), 7.52(1H, dd, J=2.8, 1.0),7.65-7.80(2H, m), 13.35 13.24 7.88(1H, d, J=16.4), 8.02-8.09(2H, m),9.01(1H, s) Ib-84 129-131 C14H10N2O1 C, 75.66; H, 4.53; C, 75.44; H,4.44; 7.23-7.30(1H, m), 7.33-7.57(4H, m), 7.62(1H, d, J=15.8), N, 12.60N, 12.50 7.69-7.78(2H, m), 7.82(1H, d, J=15.6), 8.68(1H, d, J=4.4) Ib-85on sale Ib-87 128-129.5 C13H9NS2 C, 64.17; H, 3.73; C, 64.17; H, 3.71;7.24(1H, d, J=16.2), 7.34-7.39(3H, m), 7.44-7.50(2H, m), 7.54 N, 5.76;S, N, 5.86; S, (1H, d, J=16.2), 7.87(1H, d, J=8.1), 7.98(1H, d, J=8.1)26.35 26.18 Ib-88 59-60 C23H23NO3 C, 76.43; H, 6.41; C, 76.63; H, 6.39;1.27(3H, t, J=7.2), 2.10-2.19(2H, m), 2.54(2H, t, J=7.2), N, 3.88 N,4.07 4.07(2H, t, J=6.2), 4.17(2H, q, J=7.2), 6.87(1H, dd, J=2.4 and8.1), 7.18-7.52(5H, m), 7.62-7.80(4H, m), 8.07-8.15(2H, m) Ib-89 157-159C21H19NO3 C, 75.66; H, 5.74; C, 75.72; H, 5.68; 2.15-2.24(2H, m),2.66(2H, t, J=7.2), 4.14(2H, t, J=6.2), N, 4.20 N, 4.23 6.86-6.90(1H,m), 7.14-7.17(1H, m), 7.29-7.31(2H, m), 7.48-7.60(3H, m), 7.68-7.80(3H,m), 8.12-8.16(2H, m) Ib-91 134-135 C15H11NS C, 75.92; H, 4.67; C, 76.00;H, 4.84; 7.25(1H, d, J=16.2), 7.34-7.37(1H, m), 7.44-7.52(3H, m), N,5.90; S, N, 5.91; S, 7.62-7.80(4H, m), 8.05-8.13(2H, m) 13.51 13.47Ib-100 101-102 C11H9NS C, 70.55; H, 4.84; C, 70.64; H, 4.84; 6.97(1H, d,J=15.7), 7.01-7.04(1H, m), 7.11-7.18(2H, m), N, 7.48; S, N, 7.52; S,7.24-7.32(2H, m), 7.61-7.67(1H, m), 7.79(1H, d, J=15.7), 17.12 17.168.58-8.59(1H, m)

TABLE 15 Ib-101 on sale Ib-102 170-172 C15H11N3O C, 72.28; H, 4.45; C,72.27; H, 4.48; 7.19(1H, d, J=16.8), 7.39(1H, dd, J=4.8 and 8.1),7.50-7.60 N, 16.86 N, 16.95 (3H, m), 7.64(1H, d, J=16.8), 7.89-7.96(1H,m), 8.09-8.19 (2H, m), 8.63(1H, d, J=4.2), 8.82(1H, s) Ib-103 142-143C16H13N3O2 C, 68.81; H, 4.69; C, 68.93; H, 4.52; 3.91(3H, s),7.08-7.14(1H, m), 7.18(1H, d, J=16.2), 7.38(1H, N, 15.04 N, 14.97 dd,J=4.8 and 8.1), 7.45(1H, t, J=8.1), 7.63(1H, d, J=16.2), 7.64-7.74(2H,m), 7.88-7.96(1H, m), 8.63(1H, dd, J=1.5 and 4.8), 8.81(1H, d, J=2.1)Ic-1 122-124 C15H13N1 C, 86.92; H, 6.32; C, 86.94; H, 6.34; 6.72(1H, d,J=15.4), 6.78(1H, d, J=15.4), 6.96(1H, d, J=10.0), N, 6.76 N, 6.837.06-7.14(1H, m), 7.24-7.50(7H, m), 7.62(1H, dt, J=1.8, 7.7), 8.57(1H,d, J=4.6) Ic-2 C16H15N1 2.38(3H, s), 6.72(1H, d, J=15.4), 6.93(1H, d,J=15.4), 6.92-7.32 (6H, m), 7.46(1H, d, J=15.0), 7.51(1H, d, J=15.4),7.63 (1H, dt, J=1.8, 7.6), 8.58(1H, d, J=4.8) Ic-4 63-64 C16H15N1 C,86.84; H, 6.83; C, 86.98; H, 6.74; 2.36(3H, s), 6.72(1H, d, J=15.2),6.75(1H, d, J=15.4), 6.96 N, 6.33 N, 6.48 (1H, d, J=15.4), 7.05-7.14(2H,m), 7.19-7.49(5H, m), 7.62 (1H, dt, J=1.8, 7.7), 8.57(1H, d, J=4.8) Ic-6126-127 C16H15N1 C, 86.84; H, 6.83; C, 86.75; H, 6.89; 2.35(3H, s),6.69(1H, d, J=15.0), 6.75(1H, d, J=15.4), 6.96 N, 6.33 N, 6.23 (1H, dd,J=15.4, 10.6), 7.06-7.10(1H, m), 7.14(2H, d, J=8.0), 7.27-7.49(2H, m),7.36(2H, d, J=8.4), 7.62(1H, dt, J=1.8, 7.7), 8.56(1H, d, J=4.2) Ic-9125-127 C16H12F3N1 C, 69.81; H, 4.39; C, 69.85; H, 4.26; 6.79(2H, d,J=15.2), 7.07(1H, dd, J=10.6, 15.4), 7.10-7.17 F, 20.70; N, F, 20.70; N,(1H, m), 7.29-7.52(2H, m), 7.54(2H, d, J=8.8), 7.59(2H, d, 5.09 5.12J=8.8), 7.65(1H, dt, J=1.8, 7.7), 8.59(1H, d, J=4.8) Ic-11 108-109C16H15N1O1 C, 80.98; H, 6.37; C, 80.87; H, 6.45; 3.82(3H, s), 6.67(1H,d, J=15.4), 6.73(1H, d, J=15.4), 6.81-6.94 N, 5.90 N, 6.07 (1H, m),6.87(2H, d, J=8.4), 7.05-7.12(1H, m), 7.27-7.48 (2H, m), 7.40(2H, d,J=8.8), 7.61(1H, dt, J=1.8, 7.7), 8.56(1H, d, J=4.8)

TABLE 16 Ic-15 110-111 C17H17N1O1 C, 81.24; H, 6.82; C, 81.40; H, 6.74;2.23(3H, s), 3.84(3H, s), 6.66(1H, d, J=15.4), 6.71(1H, d, N, 5.57 N,5.57 J=15.4), 6.79(1H, d, J=7.6), 6.87(1H, dd, J=10.2, 15.4), 7.05-7.11(1H, m), 7.23-7.31(3H, m), 7.41(1H, dd, J=9.8, 15.4), 7.61(1H, dt,J=1.8, 7.6), 8.56(1H, d, J=4.8) Ic-18 116-117 C18H17N1O3 C, 73.20; H,5.80; C, 73.01; H, 5.72; 2.31(3H, s), 3.88(3H, s), 6.73(2H, d, J=15.8),6.88-7.02(3H, N, 4.74 N, 4.84 m), 7.03(1H, d, J=1.2), 7.08-7.15(1H, m),7.30(1H, d, J=8.0), 7.43(1H, dd, J=10.2, 15.0), 7.63(1H, dt, J=1.8,7.6), 8.57(1H, d, J=4.4) Ic-19 147-148 C16H15N1O2 C, 75.87; H, 5.97; C,75.77; H, 6.05; 3.94(3H, s), 5.83(1H, br.s), 6.68(1H, d, J=15.4),6.70(1H, N, 5.53 N, 5.58 d, J=15.4), 6.85(1H, dd, J=10.0, 15.4),6.86-7.01(2H, m), 6.97(1H, d, J=1.2), 7.06-7.12(1H, m), 7.29(1H, d,J=8.0), 7.41(1H, dd, J=10.2, 15.4), 7.62(1H, dt, J=1.8, 7.6), 8.56 (1H,d, J=4.4) Ic-39 111-112 C15H12N2O2 C, 71.42; H, 4.79; C, 71.42; H, 4.79;6.81(1H, d, J=15.4), 6.95(1H, d, J=15.4), 7.01(1H, d, J=15.4), N, 11.10N, 11.07 7.11-7.18(1H, m), 7.25-7.75(6H, m), 7.93(1H, dd, J=1.2, 8.0),8.59(1H, d, J=4.8) Ic-40 174-175 C15H12N2O2 C, 71.42; H, 4.79; C, 71.45;H, 4.64; 6.81(2H, d, J=15.4), 6.84(1H, d, J=15.4), 7.12(1H, d, J=15.4),N, 11.10 N, 11.09 7.17-7.26(1H, m), 7.31-7.49(2H, m), 7.58(2H, d,J=8.8), 7.67(1H, dt, J=1.8, 7.6), 8.21(2H, d, J=8.8), 8.61(1H, d, J=4.8)Ic-41 122-123 C15H12F1N1 C, 79.98; H, 5.37; C, 80.07; H, 5.31; 6.71(1H,d, J=15.4), 6.93(1H, d, J=15.8), 6.85-6.93(1H, m), F, 8.43; N, F, 8.43;N, 7.01(2H, d, J=8.8), 7.08-7.14(1H, m), 7.28-7.48(2H, m), 7.41 6.226.21 (2H, d, J=8.2), 7.63(1H, dt, J=1.8, 7.8), 8.57(1H, d, J=4.4)

TABLE 17 Ic-44 124-126 C16H15N1S1 C, 75.85; H, 5.97; C, 75.82; H, 5.82;2.49(3H, s), 6.71(1H, d, J=15.4), 6.73(1H, d, J=15.4), 6.96 N, 5.53; S,N, 5.67; S, (1H, dd, J=10.6, 15.4), 7.07-7.14(1H, m), 7.21(2H, d,J=8.4), 12.66 12.66 7.26-7.49(2H, m), 7.38(2H, d, J=8.4), 7.62(1H, dt,J=1.8, 7.7), 8.56(1H, d, J=4.4) Ic-45 195-199 C17H16N2O1 C, 77.25; H,6.10; C, 77.09; H, 5.99; 2.18(3H, s), 6.70(1H, d, J=15.4), 6.73(1H, d,J=15.4), 6.87-7.00 N, 10.60 N, 10.78 (1H, m), 7.06(1H, m), 7.25-7.55(2H,m), 7.41(2H, d, J=9.2), 7.49(2H, d, J=9.2), 7.62(1H, dt, J=1.8, 7.7),8.57(1H, d, J=4.4) Ic-46 165-167 C17H18N2 C, 81.56; H, 7.25; C, 81.58;H, 7.19; 2.98(6H, s), 6.62(2H, d, J=15.0), 6.70-6.89(3H, m), 7.02-7.09N, 11.19 N, 11.12 (1H, m), 7.29-7.47(2H, m), 7.36(2H, d, J=8.8),7.59(1H, dd, 1.8, 7.9), 8.54(1H, d, J=4.2) Ic-47 on sale Ic-48 119-121C14H12N2 C, 80.74; H, 5.81; C, 80.98; H, 5.78; 6.83(1H, d, J=11.6),6.84(1H, d, J=11.4), 7.10-7.16(2H, m), N, 13.45 N, 13.29 7.31-7.41(2H,m), 7.48(2H, dd, J=3.0, 11.4), 7.64(2H, dt, J=1.8, 7.7), 8.59(2H, d,J=4.8) Ic-54 87-88 C14H12N2 C, 80.74; H, 5.81; C, 80.78; H, 5.74;6.75(1H, d, J=10.4), 6.77(1H, d, J=10.2), 7.00-7.16(2H, m), N, 13.45 N,13.58 7.24-7.33(2H, m), 7.45(1H, dd, J=7.0, 10.4), 7.64(1H, dt, J=1.0,5.1), 7.77(1H, td, J=1.2, 5.4), 8.48(1H, d, J=3.0), 8.59(1H, td, J=1.2,3.2), 8.59(1H, s) Ic-59 112-114 C14H12N2 C, 80.74; H, 5.81; C, 80.82; H,5.80; 6.69(1H, d, J=15.4), 6.82(1H, d, J=15.4), 7.10-7.18(2H, m), N,13.45 N, 13.26 7.23-7.34(1H, m), 7.30(2H, d, J=6.2), 7.46(1H, dd,J=11.0, 15.4), 7.65(1H, dt, J=1.8, 7.7), 8.56(2H, d, J=6.2), 8.60 (1H,d, J=4.8) Ic-68 118-120 C18H14N2 C, 83.69; H, 5.46; C, 84.14; H, 5.35;6.95(2H, d, J=15.0), 7.08(1H, dd, J=9.9, 15.6), 7.29-7.40 N, 10.84 N,10.92 (3H, m), 7.51(2H, dd, J=1.8, 8.7), 7.65-7.77(3H, m), 8.02-8.06(2H, m), 8.95(1H, s) Ic-71 61-62 C16H15N1 C, 86.84; H, 6.83; C, 86.79;H, 6.87; 2.15(3H, d, J=1.0), 6.73(1H, d, J=16.2), 6.79(1H, s), 7.07-7.14N, 6.33 N, 6.51 (1H, m), 7.25-7.37(6H, m), 7.46(1H, d, J=15.8), 7.63(1H,dt, J=1.8, 7.7), 8.58(1H, d, J=4.6)

TABLE 18 Ic-72 C20H23N1 0.91(3H, t, J=7.0), ca.1.38(4H), ca.1.60(2H),2.57(2H, t, J=8.1), 6.73(1H, d, J=15.8), 6.74(1H, s), 7.07-7.14(1H, m),7.28-7.39(7H, m), 7.63(1H, dt, J=1.8, 7.7), 8.57(1H, d, J=4.2) Ic-73113-114 C15H12Br1N1 C, 62.96; H, 4.23; C, 62.97; H, 4.27; 7.09(1H, d,J=14.2), 7.15-7.21(1H, m), 7.22(1H, s), 7.30-7.45 Br, 27.92; N, Br,27.63; (4H, m), 7.56(1H, d, J=14.8), 7.66(1H, dt, J=1.8, 7.7), 4.89 N,5.11 7.73-7.78(2H, m), 8.59(1H, d, J=4.2) Ic-74 C21H17N1 6.82(1H, d,J=15.4), 6.93(1H, d, J=11.0), 7.02-7.08(1H, m), 7.22-7.43(12H, m),7.56(1H, dt, J=1.8, 7.7), 8.49(1H, d, J=4.2) Ic-75 C16H15N1 2.32(3H, 8),6.67(1H, s), 6.73(1H, d, J=5.4), 7.06-7.13(1H, m), 7.27-7.40(4H, m),7.49-7.54(2H, m), 7.62(1H, dt, J=1.8, 7.4), 7.72(1H, dd, J=11.8, 15.0),8.58(1H, d, J=4.8) Ic-76 124-126 C16H15N1 (CO2H)2 C, 69.44; H, 5.50; C,69.61; H, 5.51; *3) 2.30(3H, s), 6.68(1H, d, J=15.0), 6.80(1H, d,J=11.0), N, 4.50 N, 4.46 7.30-7.42(3H, m), 7.55-7.60(2H, m), 7.65(1H, t,J=6.6), 7.83 (1H, dd, J=11.0, 15.4), 8.05(1H, d, J=8.4), 8.31(1H, dt,J=1.8, 7.2), 8.38(1H, d, J=5.8) Ic-77 94-95 C16H12N2 C, 82.73; H, 5.21;C, 82.71; H, 5.16; 7.15(1H, d, J=15.4), 7.21-7.28(1H, m), 7.25(1H, s),7.36-7.49 N, 12.06 N, 12.18 (3H, m), 7.55-7.67(3H, m), 7.76(1H, dt,J=1.8, 7.2), 8.22 (1H, d, J=11.4), 8.61(1H, d, J=4.8) Ic-78 86-88C13H11N1O1 C, 79.17; H, 5.62; C, 79.20; H, 5.45; 6.35(1H, d, J=3.2),6.42(1H, dd, J=1.8, 3.2), 6.56(1H, d, J=15.4), N, 7.10 N, 7.11 6.70(1H,d, J=15.4), 6.90(1H, dd, J=11.0, 15.4), 7.06-7.13 (1H, m), 7.26-7.45(2H,m), 7.39(1H, d, J=1.8), 7.61 (1H, dt, J=1.8, 7.7), 8.56(1H, d, J=4.8)Ic-79 96-98 C13H11N1O1 C, 79.17; H, 5.62; C, 79.38; H, 5.55; 6.65(2H, d,J=15.0), 6.66-6.70(2H, m), 7.06-7.13(1H, m), N, 7.10 N, 7.207.26-7.44(3H, m), 7.05(1H, s), 7.61(1H, dt, J=1.8, 7.7), 8.56 (1H, d,J=4.8) Ic-80 180-181 C13H11N1O1 C, 65.55; H, 5.29; C, 65.80; H, 5.56;*3) 6.67(2H, d, J=12.2), 6.80(1H, dd, J=7.0, 10.4), 6.95(1H, HCl 0.25H2OCl, 14.37; N, Cl, 14.37; d, J=10.2), 7.49-7.68(4H, m), 8.08(1H, d,J=5.4), 8.36 5.88 N, 5.71 (1H, t, J=5.4), 8.43(1H, d, J=4.0)

TABLE 19 Ic-81 115-117 C13H11N1S1 C, 73.20; H, 5.20; C, 73.37; H, 5.11;6.68(1H, d, J=15.4), 677-6.88(2H, m), 6.96-7.05(2H, m), 7.07-7.13 N,6.57; S, N, 6.62; S, (1H, m), 7.19-7.29(2H, m), 7.39(1H, dd, J=10.0,15.0), 15.03 14.79 7.62(1H, dt, J=1.8, 7.7), 8.56(1H, d, J=4.4) Ic-82120-122 C13H11N1O1 C, 73.20; H, 5.20; C, 73.50; H, 5.20; 6.69(1H, d,J=15.4), 6.80(1H, s), 6.82(1H, d, J=3.8), 7.07-7.13 N, 6.57; S, N, 6.46;S, (1H, m), 7.23-7.46(5H, m), 7.62(1H, dt, J=1.8, 7.6), 15.03 14.898.57(1H, d, J=4.6) Ic-83 71-73 C14H13N1S1 C, 73.97; H, 5.76; C, 73.80;H, 5.75; 2.27(3H, s), 6.66(1H, d, J=15.4), 6.70(1H, d, J=15.2), 6.81 N,6.16; S, N, 6.26; S, (1H, d, J=5.2), 6.94(1H, d, J=15.0), 7.11(1H, d,J=5.2), 7.26 14.10 14.13 (1H, d, J=4.8), 7.43(1H, dd, J=10.6, 15.2),7.61(1H, dt, J=1.8, 7.6), 8.56(1H, d, J=4.8) Ic-84 112-113 C12H10N2S1 C,67.26; H, 4.70; C, 67.47; H, 4.61; 6.84(1H, d, J=15.0), 6.98(1H, d,J=15.0), 7.12-7.19(1H, m), N, 13.07; S, N, 13.02; S, 7.21-7.39(3H, m),7.45(1H, dd, J=10.6, 14.6), 7.66(1H, dt, 14.96 14.99 J=1.8, 7.7),7.80(1H, d, J=3.4), 8.59(1H, d, J=4.8) Ic-85 160-162 C13H13N3 C, 73.91;H, 6.20; C, 73.64; H, 6.07; 2.32(3H, s), 6.61(1H, d, J=15.4), 6.67(1H,d, J=15.4), 6.81-6.94 N, 19.89 N, 19.76 (1H, m), 7.05-7.12(1H, m),7.26-7.30(1H, m), 7.40(1H, dd, J=10.2, 15.0), 7.56(1H, s), 7.61(1H, dt,J=1.8, 7.6), 8.54(1H, d, J=4.8) Ic-93 154-155 C15H13N1O1 C, 80.69; H,5.87; C, 80.65; H, 5.85; 6.49-6.63(5H, m), 6.62(1H, d, J=15.8),7.05-7.12(1H, m), 7.26-7.33 N, 6.27 N, 6.29 (2H, m), 7.38(1H, m),7.47(1H, s), 7.61(1H, dt, J=1.8, 7.6), 8.55(1H, d, J=4.2) Ic-109 on saleIc-110 114 C16H13N1O1 C, 81.68; H, 5.57; C, 81.74; H, 5.36; 5.10(2H, s),6.50(1H, d, J=16.2), 6.62(1H, s), 6.80-6.92(2H, N, 5.95 N, 5.91 m),7.03-7.16(3H, m), 7.31(1H, d, J=7.4), 7.37(1H, d, J=15.8), 7.64(1H, dt,J=1.8, 7.7), 8.58(1H, d, J=4.6) Ic-111 137.5-139.5 C16H11NSC12 C, 60.00;H, 3.46; C, 59.97; H, 3.51; 3.76(2H, s), 6.92(1H, d, J=15.9),7.13-7.26(3H, m), 7.60(1H, N, 4.37; S, N, 4.23; S, d, J=8.1),7.66-7.71(1H, m), 7.79(1H, d, J=2.1), 8.05(1H, 10.01; Cl, 22.14 10.07;Cl, 22.14 d, J=15.9), 8.63(1H, d, J=4.5)

TABLE 20 Id-1 C14H13N1 3.59(2H, d, J=6.6), 6.52(1H, d, J=15.8), 6.88(1H,td, J=6.8, 15.8), 7.05-7.11(1H, m), 7.21-7.35(6H, m), 7.59(1H, dt,J=1.8, 7.6), 8.52(1H, d, J=4.8) Id-2 C15H15N1 C, 86.08; H, 7.22; C,85.93; H, 6.78; 2.52-2.64(2H, m), 2.83(2H, t, J=7.5), 6.51(1H, d,J=15.4), N, 6.69 N, 6.64 6.78(1H, dt, J=15.8, 6.6), 7.05-7.14(1H, m),7.18-7.35 (5H, m), 7.29(1H, m), 7.59(1H, dt, J=1.8, 7.7), 8.52(1H, d,J=4.2) Id-4 133-140 C13H11NS-HCl C, 62.52; H, 4.84; C, 62.48; H, 4.66;7.19(1H, d, J=15.3), 7.31(1H, d, J=15.3), 7.33-7.46(3H, m), N, 5.61; Cl,N, 5.58; Cl, 7.48-7.68(4H, m), 8.04-8.13(1H, m), 8.67(1H, dd, J=2.114.19; S, 12.84 14.11; S, 12.81 and 6.0) Id-6 80-81 C14H12N2 C, 80.74;H, 5.81; C, 80.52; H, 5.91; 7.11(1H, d, J=8.8), 7.13-7.30(2H, m),7.19(1H, d, J=8.8), N, 13.45 N, 13.31 7.35-7.46(3H, m), 7.54-7.59(2H,m), 7.74(1H, dt, J=1.8, 7.7), 8.47(1H, d, J=4.6), 9.01(1H, d, J=8.2)

Experiment 1 Activity to Enhance the Expression of Human apoAI

The promoter region of the gene encoding human apoAI was isolated, andligated upstream the structure gene of firefly luciferase to construct areporter plasmid. The reporter plasmid and a marker plasmid conferringthe neomycin resistance were co-infected to cell lines derived fromhuman hepatoma, HepG2 cells, and the cell lines were incubated in aselection medium comprising DMEM medium containing 10% fetal calf serumsupplemented with G418 (Final concentration: 0.7 mg/mL, Gibco) to giveestablished strains that stably expressed the reporter molecule. Thestrains were seeded to a 96-well culture plates at a density of 50,000cells per well, and incubated for 48 hours at 37° C. under an atmosphereof 5% carbon dioxide. Then, a solution of the compounds according to theinvention in DMSO was added to the wells at final concentrations of 0 to10 μg/mL. After further incubation for 24 hours, the cells were addedwith a luciferase assay reagent (Piccagene LT 7.5 registered trade mark,Toyo Ink, KK), and the luciferase activity was determined using aluminometer (MicroBeta™ TRILUX, 1 sec/well, Wallac). The concentrationof the compounds, which intensified the luciferase activity twicecompared to that of control (DMSO without any compound of the inventionadded) was set as the minimal effective dose (MED). The results areshown in Table 21.

TABLE 21 MED (μg/ml) Ia-1 0.53 Ia-3 0.12 Ia-6 1.5 Ia-13 0.5 Ia-14 0.41Ia-15 0.57 Ia-16 1.6 Ib-1 1.1 Ib-9 0.71 Ib-50 1.2 Ib-56 0.13 Ib-57 0.12Ib-58 0.3 Ib-60 0.15 Ib-61 0.05 Ib-64 0.24 Ib-65 0.06 Ib-66 0.1 Ib-670.08 Ib-68 0.2 Ib-69 0.1 Ib-70 0.07 Ib-72 0.7 Ib-73 1.5 Ib-75 0.28 Ib-771.3 Ib-85 0.02 Ib-91 0.7 Ic-1 0.78 Ic-6 0.46 Ic-9 0.15 Ic-11 0.39 Ic-181.9 Ic-19 1.7 Ic-40 0.5 Ic-41 0.12 Ic-44 0.52 Ic-46 0.38 Ic-48 0.68Ic-54 0.49 Ic-59 1.5 Ic-68 0.38 Ic-75 1.3 Ic-76 0.23 Ic-78 0.95 Ic-791.2 Ic-82 1.2 Ic-84 1.2 Id-2 3.5 Id-4 1.0

Table 21 shows that the compounds according to the invention can promotethe function of the gene encoding human apoAI, thereby enhancing theexpression of apoAI.

Formulation 1 Tablets compound (I-1) 15 mg starch 15 mg lactose 15 mgcrystalline cellulose 19 mg polyvinyl alcohol  3 mg distilled water  30mL calcium stearate  3 mg

The ingredients other than calcium stearate were mixed uniformly, andthe mixture was powdered, granulated, and dried to give granules havinga suitable size. Then, the calcium stearate was added and the mixturewas compressed to give a tablet formulation.

Formulation 2 Capsules compound (I-2) 10 mg magnesium stearate 10 mglactose 80 mg

The ingredients were homogeneously mixed to give powders or fineparticles, which were formed into a powder formulation. This was filledin capsules to give a capsule formulation.

Formulation 3 Injectable solutions compound (I-3)  3 mg gelatin 150 mgphenol  4 mg

The ingredients were dissolved in 1 ml of distilled water for injection.The solution was sterilized by filtration, and filled into vials.

Formulation 4 Granules compound (I-4)  30 g lactose 265 g magnesiumstearate  5 g

The ingredients were mixed thoroughly, and the mixture was compressed,powdered, granulated and sieved to give a granule formulation.

INDUSTRIAL APPLICABILITY

As is apparent from the experiment as described above, the compoundsaccording to the invention have an activity for enhancing the expressionof apoAI. Thus, the compounds according to the invention are useful aspharmaceutical compositions for preventing and/or treating dyslipidemiaor arteriosclerotic diseases, and in a method and use therefor.

The invention claimed is:
 1. A method of enhancing the expression ofapoAI, which comprises administrating a compound of formula (I):

in which Ar¹ and Ar² are independently phenyl, or a monocyclic orbicyclic aromatic heterocyclic group, wherein said groups are optionallysubstituted with a substituent selected from the group consisting ofhalogen; hydroxy; lower alkyl optionally substituted with halogen,hydroxy, or lower alkoxy; lower alkoxy optionally substituted withhalogen, hydroxy, carboxy, or lower alkoxycarbonyl; lower alkenyloptionally substituted with halogen or hydroxy; lower alkenyloxyoptionally substituted with halogen or hydroxy; lower alkylthio;non-aromatic carbocyclic group optionally substituted with halogen,hydroxy, or lower alkyl; acyl; acyloxy; carboxy; lower alkoxycarbonyl;lower alkenyloxycarbonyl; amino optionally substituted with lower alkylor acyl; hydrazino; nitro; cyano; phenyl or naphthyl optionallysubstituted with halogen, hydroxy, lower alkyl or lower alkoxy; aheterocyclic group; phenoxy optionally substituted with halogen,hydroxy, or lower alkyl; a monocyclic aromatic heterocyclic oxy; oxo;and alkylenedioxy optionally substituted with lower alkyl, lower alkoxy,or phenyl; —X— is a group of formula (α):

wherein the broken line is the presence or absence of a bond; -Q= is agroup of

when the broken line is the presence of a bond; the wavy line representsa cis- or trans-geometrical isomerism with respect to the double bond;and -Q- is —CY²Y³— or —NY⁴— when the broken line is the absence of abond; or —X— is -β- wherein -β- is —CY²Y³—, —NY⁴—, —S— or —O—; Y¹, Y²,Y³, Z¹ and Z² are independently hydrogen, halogen, lower alkyl, carboxy,lower alkoxycarbonyl, a monocyclic carbocyclic group, or a monocyclicheterocyclic group, wherein said lower alkyl and lower alkoxycarbonylare optionally substituted with a substituent selected from the groupconsisting of halogen, hydroxy, lower alkoxy, a monocyclic or bicycliccarbocyclic group, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino,lower alkylamino, nitro, and a monocyclic or bicyclic heterocyclicgroup, wherein said monocyclic carbocyclic group and said monocyclicheterocyclic group are optionally substituted with a substituentselected from the same group as the substituent of phenyl describedabove, and two Y¹s or more and two Z¹s or more each may be different oneanother; Y⁴ is hydrogen or lower alkyl; m is 0 or 1; n is 0, 1, or 2;provided that, when n is 0, then m is 1 and —X— is a group of formula(α); the wavy line represents a cis- or trans-geometrical isomerism withrespect to the double bond; provided that: (a) when both Ar¹ and Ar² aresubstituted or unsubstituted phenyl, then none of Y¹, Y², Z¹ and Z² canbe substituted or unsubstituted phenyl; or (b) when either Ar¹ or Ar² issubstituted phenyl, the substituent is independently selected from thegroup consisting of halogen; lower alkyl optionally substituted withhalogen, hydroxy, or lower alkoxy; lower alkenyl optionally substitutedwith halogen or hydroxy; lower alkenyloxy optionally substituted withhalogen or hydroxy; lower alkylthio; non-aromatic carbocyclic groupoptionally substituted with halogen, hydroxy, or lower alkyl; acyl;acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; aminooptionally substituted with lower alkyl or acyl; hydrazino, nitro;cyano; phenyl or naphthyl optionally substituted with halogen, hydroxy,lower alkyl or lower alkoxy; a heterocyclic group; a monocyclic aromaticheterocyclic oxy; oxo; and alkylenedioxy optionally substituted withlower alkyl, lower alkoxy, or phenyl; or a pharmaceutically acceptablesalt thereof, to a patient who needs treatment of dyslipidemia orarteriosclerotic diseases.
 2. The method according to claim 1, in whichat least one of Ar¹ and Ar² in formula (I) is a monocyclic or bicyclicaromatic heterocyclic group that may be optionally substituted, and thatcontains a nitrogen atom at the position adjacent to the constituentatom of the ring that has a binding bond.
 3. The method according toclaim 1, in which at least one of Ar¹ and Ar² in formula (I) is2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2-benzisoxazolyl, 2-benzothiazolyl,or 2-benzimidazolyl, each of which may be optionally substituted.
 4. Themethod according to claim 2 or 3, in which one of Ar¹ and Ar² in formula(I) is a group as defined in claim 2 or 3, and the other is a phenylthat may be optionally substituted, or a monocyclic or bicyclic aromaticheterocyclic group that may be optionally substituted.
 5. The methodaccording to claim 2 or 3, in which one of Ar¹ and Ar² in formula (I) isa group as defined in claim 2 or 3, and the other is a phenyl or amonocyclic or bicyclic aromatic heterocyclic group, each of which may beoptionally substituted, wherein the substituent is a halogen; a loweralkyl optionally substituted by a halogen or a lower alkoxy; a hydroxy;a lower alkoxy; a phenyloxy; a naphtylthio; an acyloxy; a carboxy; alower alkoxycarbonyl; an amino optionally substituted by a lower alkylor a lower acyl; a phenyl that may be optionally substituted by a loweralkoxy; a nitro; a lower alkylthio; a cyano; a monocyclic heterocyclicgroup; or an alkylenedioxy that may be substituted by a lower alkyl, alower alkoxy or phenyl.
 6. The method according to any one of claims 1to 3, in which Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen.
 7. Themethod according to any one of claims 1 to 3, in which Z¹, and Z² informula (I) is a hydrogen.
 8. The method according to any one of claims1 to 3, in which m in formula (I) is 1, —X— is a group of formula (α),the broken line is the presence of a bond, -Q= is a group of

and Y² is a hydrogen.
 9. The method according to any one of claims 1 to3, in which m and n in formula (I) are 1, and —X— is -β-.
 10. The methodaccording to claim 4, in which Y¹, Y², Y³, and Y⁴ in formula (I) is ahydrogen.
 11. The method according to claim 5, in which Y¹, Y², Y³, andY⁴ in formula (I) is a hydrogen.
 12. The method according to claim 4, inwhich Z¹, and Z² in formula (I) is a hydrogen.
 13. The method accordingto claim 5, in which Z¹, and Z² in formula (I) is a hydrogen.
 14. Themethod according to claim 6, in which Z¹, and Z² in formula (I) is ahydrogen.
 15. The method according to claim 4, in which Z¹ in formula(I) is a linker group comprising 1 to 2 atoms that combines with theconstituent atoms of the ring Ar² that are bonded to Z¹ via the twoatoms to form a condensed ring.
 16. The method according to claim 5, inwhich Z¹ in formula (I) is a linker group comprising 1 to 2 atoms thatcombines with the constituent atoms of the ring Ar² that are bonded toZ¹ via the two atoms to form a condensed ring.
 17. The method accordingto claim 6, in which Z¹ in formula (I) is a linker group comprising 1 to2 atoms that combines with the constituent atoms of the ring Ar² thatare bonded to Z¹ via the two atoms to form a condensed ring.
 18. Themethod according to claim 4, in which m in formula (I) is 1, —X— is agroup of formula (α), the broken line is the presence of a bond, -Q= isa group of

and Y² is a hydrogen.
 19. The method according to claim 5, in which m informula (I) is 1, —X— is a group of formula (α), the broken line is thepresence of a bond, -Q= is a group of

and Y² is a hydrogen.
 20. The method according to claim 6, in which m informula (I) is 1, —X— is a group of formula (α), the broken line is thepresence of a bond, -Q= is a group of

and Y² is a hydrogen.
 21. The method according to claim 7, in which m informula (I) is 1, —X— is a group of formula (α), the broken line is thepresence of a bond, -Q= is a group of

and Y² is a hydrogen.
 22. The method according to claim 4, in which m informula (I) is 1, —X— is a group of formula (α), and Z² is a linkergroup comprising 1 to 2 atoms that combines with the constituent atomsof the ring Ar¹ to form a condensed ring.
 23. The method according toclaim 5, in which m in formula (I) is 1, —X— is a group of formula (α),and Z² is a linker group comprising 1 to 2 atoms that combines with theconstituent atoms of the ring Ar¹ to form a condensed ring.
 24. Themethod according to claim 6, in which m in formula (I) is 1, —X— is agroup of formula (α), and Z² is a linker group comprising 1 to 2 atomsthat combines with the constituent atoms of the ring Ar¹ to form acondensed ring.
 25. The method according to claim 4, in which m and n informula (I) are 1, and —X— is -β-.
 26. The method according to claim 5,in which m and n in formula (I) are 1, and —X— is -β-.
 27. The methodaccording to claim 6, in which m and n in formula (I) are 1, and —X— is-β-.
 28. The method according to claim 7, in which m and n in formula(I) are 1, and —X— is -β-.